Tetrahydro-1H-cyclopenta[cd]indene derivatives as hypoxia inducible factor-2α inhibitors

ABSTRACT

The present disclosure provides certain tetrahydro-1H-cyclopenta[cd]indene compounds that are Hypoxia Inducible Factor 2α (HIF-2α) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of HIF-2α. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 16/851,018, filed onApr. 15, 2020, which is an International Application claiming thebenefit of U.S. Provisional Application No. 62/836,019 filed Apr. 18,2019, and U.S. Provisional Application No. 62/946,191 filed Dec. 10,2019; the entireties of which are herein incorporated by reference.

FIELD OF THE DISCLOSURE

The present disclosure provides certaintetrahydro-1H-cyclopenta[cd]indene compounds that are Hypoxia InducibleFactor 2α (HIF-2α) inhibitors and are therefore useful for the treatmentof diseases treatable by inhibition of HIF-2α. Also provided arepharmaceutical compositions containing such compounds and processes forpreparing such compounds.

BACKGROUND

Hypoxia is as an important regulator of both physiological andpathological processes, including various types of cancer, liver diseasesuch as nonalcoholic steatohepatitis (NASH), inflammatory disease suchas inflammatory bowel disease (IBD), pulmonary diseases such aspulmonary arterial hypertension (PAH), and iron load disorders.

Hypoxia is well-known to drive cancer progression and is associated withpoor patient prognosis, resistance to chemotherapy and radiationtreatment. With the progress over the past several decades inelucidating molecular mechanisms that enable cellular adaptation tochronic oxygen deprivation, there is a strong interest in developingdrugs that can effectively block the hypoxic response pathway in tumors.Among signaling modules, involved in the hypoxic response, that havebeen explored as therapeutic targets for treating cancer, HIF-α proteinscontinue to draw interest as they offer the possibility to broadlyinhibit downstream hypoxia effects within both tumor and tumormicroenvironment. Thus, directly targeting HIF-α proteins offers anexciting opportunity to attack tumors on multiple fronts (see Keith, etal. Nature Rev. Cancer 12: 9-22, 2012).

Hypoxia-Inducible Factors (HIF-1α and HIF-2α) are key transcriptionfactors in the hypoxia pathway, therefore serve as attractive targetsfor therapeutic intervention. The half-life of HIF-α proteins is tightlyregulated by the oxidative status within the cell. Under normoxicconditions, HIF-specific prolyl-hydroxylases (PHD) hydroxylates specificproline residues on the HIF proteins, which is then recognized by thetumor suppressor von Rippel-Lindau (VHL). The binding of VHL furtherrecruits E3 ubiquition-ligase complex that targets HIF-α proteins forproteasome mediated degradation. Under hypoxic conditions, when PHDs areinhibited as they require oxygen to be functional, HIF-α proteinsaccumulate and enter the nucleus to actively drive gene expression. Inaddition, genetic mutations of the VHL gene which result in loss of VHLfunction lead to constitutively active HIF-α proteins independent ofoxygen levels. Upon activation, these transcription factors stimulatethe expression of genes that collectively regulate anaerobic metabolism,angiogenesis, cell proliferation, cell survival, extracellular matrixremodeling, pH homeostasis, amino acid and nucleotide metabolism, andgenomic instability.

Both HIF-1α and HIF-2a dimerize with HIF-1β (also named as ARNT: arylhydrocarbon receptor nuclear translocator) and the dimer subsequentlybinds to hypoxia response elements (HRE) on target genes. The expressionof HIF-113 is independent of oxygen levels or VHL status, thus,transcriptional activity of the complex is primarily controlled by theavailability of the HIF-α proteins. HIF-1α and HIF-2a differ in theirtissue distribution, sensitivity to hypoxia, timing of activation andtarget gene specificity (Hu, et al. Mol. Cell Biol. 23: 9361-9374, 2003and Keith, et al. Nature Rev. Cancer 12: 9-22, 2012). Whereas HIF-1αmRNA is ubiquitously expressed, the expression of HIF-2α mRNA is foundpredominantly in kidney fibroblasts, hepatocytes and intestinal lumenepithelial cells. Neither HIF-α is detected in normal tissue with theexception of HIF-2α, which is expressed in macrophages (see Talks, etal. Am. J. Pathol. 157: 411-421, 2000). In response to hypoxia, HIF-1αexhibits a transient, acute transcriptional response. In contrast,HIF-2a presents a more prolonged transcriptional effect. Furthermore,HIF-2a has greater transcriptional activity than HIF-1α under moderatelyhypoxic conditions like those encountered in end capillaries (seeHolmquist-Menge/bier, et al. Cancer Cell 10: 413-423, 2006). Althoughsome hypoxia-regulated genes are regulated by both HIF-1α and HIF-2α,certain genes are only responsive to a specific HIF-α protein. Forexample, lactate dehydrogenase A (LDHA), phosphoglycerate kinase (PGK)and pyruvate dehydrogenase kinase 1 (PDK1) are mostly controlled byHIF-1α, while Oct-4 and erythropoietin (EPO) are exclusively regulatedby HIF-2α.

In general, the relative contributions of HIF-α proteins on genetranscription are both cell type specific, and disease specific. Infact, there are reports supporting the HIF-α proteins playingconflicting roles in tumorigenesis. One example is the regulation ofHIF-α on MYC, which is an important transcription factor and frequentlyoverexpressed in human cancers. It has been shown that HIF-2α activationincreases MYC transcription activity, while HIF-1α inhibits MYCactivity. As a result, in MYC driven tumors, HIF-2α inhibition decreasedproliferation whereas HIF-1α inhibition increased growth (see Gordan, etal. Cancer Cell 11: 335-347, 2007 and Koshiji et al. EMBO J. 23:1949-1956, 2004). Therefore, identification of small molecules thatspecifically inhibit HIF-2α activity is desirable. In addition, HIF-2αis demonstrated to be a key driver of Clear Cell Renal Cell Carcinoma(ccRCC) with VHL deficiency and several other pseudohypoxic tumorsincluding but not limited to glioblastoma, neuroblastoma,somatostatinomas, leiomyomas/leiomyosarcomas, polycythaemia and retinalabnormalities etc. Thus, an HIF-2α inhibitor will offer therapeuticbenefits with limited toxicity than a pan-HIF-α inhibitor.

In addition to a direct role in regulating growth-promoting genes intumor cells (e.g. ccRCC), HIF-2α also mediates the immunosuppressiveeffect of hypoxia on the tumor microenvironment. Expression of HIF-2αhas been detected in cells of the myeloid lineage, and accumulation ofHIF-2a protein has been readily detected in various human cancers (seeTalks K L, et al. Am J Pathol. 2000; 157(2):411-421). Overexpression ofHIF-2α in tumor-associated macrophages (TAMs) is associated withhigh-grade human tumors and is correlated with poor prognosis.Mechanistically, HIF-2α promotes the polarization of macrophages to theimmunosuppressive M2 phenotype and enhances migration and invasion oftumor-associated macrophages (see Imtiyaz H Z et al. J Clin Invest.2010; 120(8):2699-2714). Furthermore, HIF-2α can indirectly promoteadditional immunosuppressive pathways (e.g. adenosine and arginase etc.)by modulating the expression of key signaling regulators such asadenosine A2B/A2A receptors and arginase. These data suggest that HIF-2αmay be a potential therapeutic target for treating a broader range ofinflammatory disorders and cancer as a single agent or in combinationwith other therapeutic agents e.g., immunotherapies.

Because of the roles of HIF-α proteins in regulating physiologicalresponse to the change of oxygen levels, they have been causallyassociated with many hypoxia-related pathological processes in additionto cancer. Inflammatory bowel disease (IBD) is a chronic relapsinginflammatory disease of the intestine. Normally, the intestines maintaina dynamic and rapid fluctuation in cellular oxygen tension, with thetips of the epithelial villi being hypoxic and the base of theepithelial villi better oxygenated. A dysregulated epithelial oxygentension plays a role in intestinal inflammation and resolution in IBD(see Shah Y. M., Molecular and Cellular Pediatrics, 2016 December;3(1):1). Even though HIF-1α and HIF-2α can bind to the same canonicalHREs, multiple studies have demonstrated that HIF-1α and HIF-2α regulatedistinct subset of genes, leading to contrasting effect in symptoms ofIBD. HIF-1α in intestinal epithelial cells is widely recognized as amajor protective factor in IBD (see Karhausen J, et al. J Clin Invest.2004; 114(8):1098-1106; Furuta G T, et al. J Exp Med. 2001;193(9):1027-1034). However, HIF-2α activation contributes to IBD throughmultiple mechanisms, including directly regulating a number ofpro-inflammatory cytokines such as tumor necrosis factor-α to driveinflammation, and indirectly disrupting intestine barrier integritythrough increasing the turnover of tight junction protein occluding (seeXue X, et al. Gastroenterology. 2013; 145(4):831-841; Glover L E, et al.Proc Natl Acad Sci USA. 2013; 110(49):19820-19825). Therefore, in IBD, aHIF-2α inhibitor holds promise of suppressing chronic activation ofHIF-2α to revert the pro-inflammatory response and increase theintestinal barrier integrity.

With the growing epidemic of obesity and metabolic syndrome, NASH isbecoming a common chronic liver disease and limited therapeutic optionsare available. A recent study has demonstrated a positive correlationbetween intestinal HIF-2α signaling with body-mass index and hepatictoxicity, with further animal model study supporting the causality ofthis correlation (see Xie C, et al. Nat Med. 2017 November;23(11):1298-1308.). Thus, targeting intestinal HIF-2α represents a noveltherapeutic strategy for NASH.

PAH is a life-threatening disease with very poor prognosis. Progressivepulmonary vascular remodeling, characterized by concentric pulmonaryarterial wall thickening and obliterative intimal lesions, is one of themajor causes for the elevation of pulmonary vascular resistance (PVR)and pulmonary arterial pressure (PAP) in patients with PAH (see AggarwalS, et al. Compr Physiol. 2013 July; 3(3):1011-34). Recently, HIF-2α isfound to contribute to the process of hypoxic pulmonary vascularremodeling, reduced plasticity of the vascular bed, and ultimately,debilitating PAH (see Andrew S., et al. Proc Natl Acad Sci USA. 2016Aug. 2; 113(31): 8801-8806, Tang H, et al. Am J Physiol Lung Cell MolPhysiol. 2018 Feb. 1; 314(2):L256-L275.). These studies have offered newinsight into the role of pulmonary endothelial HIF-2α in regulating thepulmonary vascular response to hypoxia, and offer a much-neededintervention therapeutics strategy by targeting HIF-2α.

Iron is an essential nutrient that is required for oxygen delivery andserves as a cofactor in many key enzymatic and redox reactions. HIF-2αregulates the expression of key genes that contribute to ironabsorption, which, when disrupted, leads to iron load disorders. Forexample, an elegant study with mice lacking HIF-2α in the intestinalepithelium showed HIF-2α knockout results in a significant decrease inthe duodenal levels of Dmt1, Dcytb and FPN mRNAs, all important genes iniron transport and absorption. More importantly, these effects were notcompensated by HIF-1α (see Mastrogiannaki M, et al. J Clin Invest. 2009;119(5):1159-1166). Thus, a small molecule that targets HIF-2α holdspotential of improving iron homeostasis in patients with iron disorders.Therefore, identification of small molecules that inhibit HIF-2αactivity is desirable. The present disclosure fulfills this and relatedneeds.

SUMMARY

In a first aspect, provided is a compound of Formula (IA):

wherein:

-   -   X¹ is CH or N;    -   R¹ is hydroxy, halo, amino, —OP(O)(OH)₂, —OCH₂OP(O)(OH)₂,        —OCOR¹⁰, —OCOOR¹¹, —OCONR¹²R¹³, —OCHR¹⁴OCOR¹⁵ or        —OCHR¹⁴OCOOR^(15a) where R¹⁰, R¹¹, and R¹⁵ and R^(15a) are        independently alkyl or alkyl substituted with amino, carboxy or        hydroxy, R¹² and R¹³ are independently hydrogen, alkyl, or alkyl        substituted with amino, carboxy or hydroxy or R¹² and R¹³        together with the nitrogen atom to which they are attached form        optionally substituted heterocyclyl, and each R¹⁴ is hydrogen,        alkyl, or haloalkyl;

R² is hydrogen, deuterium, alkyl, halo, haloalkyl, alkenyl, or alkynyl;

R^(2a) is hydrogen, halo, or deuterium;

R³ and R⁴ are independently hydrogen, deuterium, alkyl, cycloalkyl,halo, haloalkyl, hydroxyalkyl, or alkoxyalkyl; or

R³ and R⁴ together with the carbon to which they are attached form oxo,3 to 6 membered cycloalkylene, or 4 to 6 membered optionally substitutedheterocyclylene;

R⁵ is hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxy, or alkoxy;

R⁶ is hydrogen, deuterium, alkyl, cycloalkyl, or halo; or

R⁵ and R⁶ together with the carbon to which they are attached form oxo,alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to 6 memberedoptionally substituted heterocyclylene; provided R⁵ and R⁶ and R³ and R⁴together with the carbon to which they are attached do not form oxo,cycloalkylene or optionally substituted 4 to 6 membered heterocyclylenesimultaneously;

R⁷ is hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, orhaloalkoxy;

L is a bond, S, SO, SO₂, O, CO, or NR¹⁶ where R¹⁶ is hydrogen or alkyl;

R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl,spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkylwherein aryl or heteroaryl, each by itself or as part of aralkyl orheteroaralkyl, or heterocyclyl by itself or as part of heterocyclylalkylis substituted with R^(a), R^(b), R^(c), R^(g) and R^(h) wherein R^(a),R^(b), and R^(c) are independently selected from hydrogen, deuterium,alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, alkylidenyl,optionally substituted aryl, optionally substituted heteroaryl, andoptionally substituted heterocyclyl and R^(g) and R^(h) areindependently selected from hydrogen, deuterium, and halo; and

R⁹ is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo,haloalkyl, haloalkoxy, alkylsulfoxide, alkylsulfonyl, or heteroarylwherein the heteroaryl is optionally substituted with R^(d), R^(e), andR^(f) independently selected from hydrogen, alkyl, haloalkyl,haloalkoxy, alkoxy, hydroxy, halo, and cyano; or

when R⁹ and R² are attached to the same carbon atom, they can combine toform oxo, alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to 6-memberedheterocyclylene;

R^(9a) is hydrogen, halo, or deuterium;

a pharmaceutically acceptable salt thereof.

In a first embodiment of the first aspect, provided is a compound ofFormula (I):

wherein:

X¹ is CH or N;

R¹ is hydroxy, halo, amino, —OP(O)(OH)₂, —OCH₂OP(O)(OH)₂, —OCOR¹⁰,—OCOOR¹¹, —OCONR¹²R¹³, —OCHR¹⁴OCOR¹⁵ or —OCHR¹⁴OCOOR^(15a) where R¹⁰,R¹¹, and R¹⁵ and R^(15a) are independently alkyl or alkyl substitutedwith amino, carboxy or hydroxy, R¹² and R¹³ are independently hydrogen,alkyl, or alkyl substituted with amino, carboxy or hydroxy or R¹² andR¹³ together with the nitrogen atom to which they are attached formoptionally substituted heterocyclyl, and each R¹⁴ is hydrogen, alkyl, orhaloalkyl;

R² is hydrogen, deuterium, alkyl, halo, haloalkyl, alkenyl, or alkynyl;

R³ and R⁴ are independently hydrogen, deuterium, alkyl, cycloalkyl,halo, haloalkyl, hydroxyalkyl, or alkoxyalkyl; or

R³ and R⁴ together with the carbon to which they are attached form oxo,3 to 6 membered cycloalkylene, or 4 to 6 membered optionally substitutedheterocyclylene;

R⁵ is hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxy, or alkoxy;

R⁶ is hydrogen, deuterium, alkyl, cycloalkyl, or halo; or

R⁵ and R⁶ together with the carbon to which they are attached form 3 to6 membered cycloalkylene or 4 to 6 membered optionally substitutedheterocyclylene; provided R⁵ and R⁶ and R³ and R⁴ together with thecarbon to which they are attached do not form cycloalkylene oroptionally substituted 4 to 6 membered heterocyclylene simultaneously;

R⁷ is hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, orhaloalkoxy;

L is a bond, S, SO, SO₂, O, CO, or NR¹⁶ where R¹⁶ is hydrogen or alkyl;

R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl,spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkylwherein aryl or heteroaryl, each by itself or as part of aralkyl orheteroaralkyl, or heterocyclyl by itself or as part of heterocyclylalkylis substituted with R^(a), R^(b), and R^(c) independently selected fromhydrogen, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, alkylidenyl,optionally substituted aryl, optionally substituted heteroaryl, andoptionally substituted heterocyclyl; and

R⁹ is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo,haloalkyl, haloalkoxy, alkylsulfoxide, alkylsulfonyl, or heteroarylwherein the heteroaryl is optionally substituted with R^(d), R^(e), andR^(f) independently selected from hydrogen, alkyl, haloalkyl,haloalkoxy, alkoxy, hydroxy, halo, and cyano; or

when R⁹ and R² are attached to the same carbon atom, they can combine toform oxo, alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to 6-memberedheterocyclylene;

a pharmaceutically acceptable salt thereof.

In a second aspect, this disclosure is directed to a method of treatinga disease treatable by inhibition of HIF2α in a patient, preferably thepatient is in need of such treatment, which method comprisesadministering to the patient, preferably a patient in need of suchtreatment, a therapeutically effective amount of a compound of Formula(IA) or (I) (or any of the embodiments thereof described herein) or apharmaceutically acceptable salt thereof.

In one embodiment of the second aspect, the disease is cancer such asrenal cancer, glioblastoma (see PNAS 2017, 114, E6137-E6146), renal cellcarcinoma, neuroblastoma, pheochromocytomas and paragangliomas (seeEuropean Journal of Cancer 2017, 86, 1-4), somatostatinomas,hemangioblastomas, gastrointestinal stromal tumors (GIST), pituitarytumors, leiomyomas, leiomyosarcomas, polycythaemia or retinal tumors. Inanother embodiment, non-cancer diseases that could benefit from Hif-2αinhibition include VHL (von Hippel-Lindau) disease (see Oncotarget,2015, 6, 23036-23037), PAH (pulmonary artery hypertension) (see Mol.Cell. Biol. 2016, 36, 1584-1594), reflux esophagitis (see CurrentOpinion in Pharmacology 2017, 37: 93-99), hepatic steatosis (see NatureMedicine 2017, 23, 1298-1308), NASH, inflammatory disease such asinflammatory bowel disease (see Nature Reviews gastroenterology &Hepatology 2017, 14, 596), autoimmune disease such asGraft-versus-Host-Disease (see Blood, 2015, 126, 1865), or ironoverload.

In a third aspect, the disclosure is directed to a pharmaceuticalcomposition comprising a compound of Formula (IA) or (I) (or any of theembodiments thereof described herein) or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable excipient.

In a fourth aspect, the disclosure is directed to a compound of Formula(IA) or (I), (or any embodiments thereof described herein) or apharmaceutically acceptable salt thereof for use as a medicament. In oneembodiment, the compound Formula (I) (and any embodiments thereofdescribed herein) or a pharmaceutically acceptable salt, is useful forthe treatment of one or more of diseases disclosed in the second aspectabove.

In a fifth aspect provided is the use of a compound of Formula (IA) or(I) or a pharmaceutically acceptable salt thereof (and any embodimentsthereof disclosed herein) in the manufacture of a medicament fortreating a disease in a patient in which the activity of HIF2αcontributes to the pathology and/or symptoms of the disease. In oneembodiment the disease is one or more of diseases disclosed in thesecond aspect above.

In a sixth aspect provided is a method of inhibiting HIF2α which methodcomprises contacting HIF2α with a compound of Formula (IA) or (I) (orany of the embodiments thereof described herein) or a pharmaceuticallyacceptable salt thereof; or contacting HIF2α with a pharmaceuticalcomposition comprising a compound of Formula (IA) or (I) (or any of theembodiments thereof described herein) or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable excipient.

In any of the aforementioned aspects involving the treatment of cancer,are further embodiments comprising administering the compound of Formula(IA) or (I) or a pharmaceutically acceptable salt thereof (or anyembodiments thereof disclosed herein) in combination with at least oneadditional anticancer agent such as an EGFR inhibitor gefitinib,erlotinib, afatinib, icotinib, neratinib, rociletinib, cetuximab,panitumumab, zalutumumab, nimotuzumab, or matuzumab. In anotherembodiment, the compound of Formula (IA) or (I) (and any embodimentsthereof described herein) or a pharmaceutically acceptable salt thereofis administered in combination with a HER2/neu inhibitor includinglapatinib, trastuzumab, and pertuzumab. In another embodiment, thecompound of Formula (IA) or (I) (and any embodiments thereof describedherein) or a pharmaceutically acceptable salt thereof is administered incombination with a PI3k/mTOR inhibitor including idelalisib, buparlisib,BYL719, and LY3023414. In another embodiment, the compound of Formula(IA) or (I) (and any embodiments thereof described herein) or apharmaceutically acceptable salt thereof is administered in combinationwith a VEGF inhibitor such as bevacizumab, and/or a multi-tyrosinekinase inhibitors such as sorafenib, sunitinib, pazopanib, andcabozantinib. In another embodiment, the compound of Formula (IA) or (I)(and any embodiments thereof described herein) or a pharmaceuticallyacceptable salt thereof is administered in combination with a animmunotherapeutic agents such as PD-1 and PD-L1 inhibitors, CTLA4inhibitors, IDO inhibitors, TDO inhibitors, A2A agonists, A2B agonists,STING agonists, RIG-1 agonists, Tyro/Axl/Mer inhibitors, glutaminaseinhibitors, arginase inhibitors, CD73 inhibitors, CD39 inhibitors, TGF-βinhibitors, IL-2, interferon, PI3K-γ inhibitors, CSF-1R inhibitors, GITRagonists, OX40 agonists, TIM-3 antagonists, LAG-3 antagonists, CAR-Ttherapies, and therapeutic vaccines. When combination therapy is used,the agents can be administered simultaneously or sequentially.

In an seventh aspect, provided is a process of making a compound ofFormula (IA) where R⁹ is hydroxy and X¹, R² is hydrogen, R¹, R³ to R⁸,L, R^(2a) and R^(9a) are as defined in the first aspect above, i.e.Formula (IA-1):

comprising treating a compound of Formula (IA) where R² and R⁹ togetherwith the carbon atom to which they are attached form oxo and X¹, R¹, R³to R⁸, L, R^(2a) and R^(9a) are as defined in the first aspect above,i.e. Formula (IA-2):

with a suitable reducing agent.

In a first embodiment of the eighth aspect, in each of the compounds ofFormula (IA-1) and (IA-2), X¹ is CH, R¹ is hydroxy, R³, R⁴, R⁵, and R⁶are fluoro, and R⁷, R^(2a) and R^(9a) are hydrogen, L is O, and R⁸ is3-cyano-5-fluorophenyl.

In a ninth aspect, provided is a process of making a compound of Formula(IA) where R² is hydrogen, R⁹ is fluoro and X¹, R¹, R³ to R⁸, L, R^(2a)and R^(9a) are as defined in the first aspect above, i.e. Formula(IA-3):

comprising treating a compound of Formula (I) where R² hydrogen and R⁹is hydroxy, and X¹, R¹, R³ to R⁸, L, R^(2a) and R^(9a) are as defined inthe first aspect above i.e. Formula (IA-1):

with a suitable fluorinating agent.

In a first embodiment of the ninth aspect, in each of the compounds ofFormula (IA-3) and (IA-1), X¹ is CH, R¹ is hydroxy, R³, R⁴, R⁵, and R⁶are fluoro, and R⁷, R^(2a) and R^(9a) are hydrogen, L is O, and R⁸ is3-cyano-5-fluorophenyl.

DETAILED DESCRIPTION

Definitions:

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this Application and have thefollowing meaning:

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl, pentyl, and the like. It will be recognized by a personskilled in the art that the term “alkyl” may include “alkylene” groups.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms unless otherwise stated e.g., methylene,ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene,pentylene, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms containing a double bond, e.g., propenyl, butenyl, andthe like.

“Alkyldienyl” is alkenyl as defined above that is attached via theterminal divalent carbon. For example, in the compound below:

the alkyldienyl group is enclosed by the box which is indicated by thearrow.

“Haloalkyldienyl” is alkyldienyl that is substituted with one or twohalo, each group as defined herein.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms containing a triple bond, e.g., propynyl, butynyl, andthe like.

“Alkylthio” means a —SR radical where R is alkyl as defined above, e.g.,methylthio, ethylthio, and the like.

“Alkylsulfonyl” means a —SO₂R radical where R is alkyl as defined above,e.g., methylsulfonyl, ethylsulfonyl, and the like.

“Alkylsulfoxide” means a —SOR radical where R is alkyl as defined above,e.g., methylsulfoxide, ethylsulfoxide, and the like.

“Amino” means a —NH₂.

“Alkylamino” means a —NHR radical where R is alkyl as defined above,e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and thelike.

“Aminoalkyl” means a linear monovalent hydrocarbon radical of one to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbons substituted with —NR′R″ where R′ and R″ are independentlyhydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or alkylcarbonyl,each as defined herein, e.g., aminomethyl, aminoethyl,methylaminomethyl, and the like.

“Alkoxy” means a —OR radical where R is alkyl as defined above, e.g.,methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, andthe like.

“Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with at least one alkoxy group, such as oneor two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or3-methoxypropyl, 2-ethoxyethyl, and the like.

“Alkoxycarbonyl” means a —C(O)OR radical where R is alkyl as definedabove, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

“Alkylcarbonyl” means a —C(O)R radical where R is alkyl as definedherein, e.g., methylcarbonyl, ethylcarbonyl, and the like.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 10 ring atoms e.g., phenyl or naphthyl.

“Aralkyl” means a -(alkylene)-R radical where R is aryl as definedabove, e.g., benzyl, phenethyl, and the like.

“Bicyclic cycloalkyl” means a fused bicyclic saturated monovalenthydrocarbon radical of six to ten carbon atoms, and is optionallysubstituted with one or two substituents independently selected fromalkyl, halo, alkoxy, hydroxy, and cyano. Examples include, but are notlimited to, decalin, octahydro-1H-indene, and the like.

“Cycloalkyl” means a monocyclic saturated monovalent hydrocarbon radicalof three to ten carbon atoms optionally substituted with one or twosubstituents independently selected from alkyl, alkyldienyl, halo,alkoxy, hydroxy, cyano, haloalkyldienyl and cyanoalkyl. Examplesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 1-cyanocycloprop-1-yl, 1-cyanomethylcycloprop-1-yl,3-fluorocyclohexyl, and the like. Cycloalkyl may include cycloalkyleneas defined herein.

“Cycloalkylalkyl” means a -(alkylene)-R radical where R is cycloalkyl asdefined above, e.g., cyclopropylmethyl, cyclohexylmethyl, and the like.

“Cycloalkylene” means a divalent cycloalkyl, as defined above, unlessstated otherwise.

“Cycloalkenyl” means a monocyclic monovalent hydrocarbon radical ofthree to ten carbon atoms containing one or two double bond(s)optionally substituted with one or two substituents independentlyselected from alkyl, halo, alkoxy, hydroxy, cyano, and cyanoalkyl.Examples include, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, or cyclohexenyl, and the like.

“Oxocycloalkenyl” means a monocyclic monovalent hydrocarbon radical ofthree to ten carbon atoms containing one or two double bond(s) and anoxo group, and is optionally substituted with one or two substituentsindependently selected from alkyl, halo, alkoxy, hydroxy, cyano, andcyanoalkyl. Examples include, but are not limited to,3-oxocyclohex-1-enyl, and the like.

“Cyanoalkyl” means a linear monovalent hydrocarbon radical of one to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbons substituted with cyano e.g., cyanomethyl, cyanoethyl, andthe like.

“Carboxy” means —COOH.

“Dialkylamino” means a —NRR′ radical where R and R′ are alkyl as definedabove, e.g., dimethylamino, methylethylamino, and the like.

“Disubstituted amino” means a —NRR′ radical where R and R′ areindependently alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, oralkylcarbonyl, each as defined herein, e.g., dimethylamino,ethylmethylamino, bis-hydroxyethylamino, bis-methoxyethylamino,diethylaminoethylamino, and the like.

“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro orchloro.

“Haloalkyl” means alkyl radical as defined above, which is substitutedwith one or more halogen atoms, e.g., one to five halogen atoms, such asfluorine or chlorine, including those substituted with differenthalogens, e.g., —CH₂Cl, —CF₃, —CHF₂, —CH₂CF₃, —CF₂CF₃, —CF(CH₃)₂, andthe like. When the alkyl is substituted with only fluoro, it can bereferred to in this Application as fluoroalkyl.

“Haloalkoxy” means a —OR radical where R is haloalkyl as defined abovee.g., —OCF₃, —OCHF₂, and the like. When R is haloalkyl where the alkylis substituted with only fluoro, it is referred to in this Applicationas fluoroalkoxy.

“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with one or two hydroxy groups, provided thatif two hydroxy groups are present they are not both on the same carbonatom. Representative examples include, but are not limited to,hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

“Heterocyclyl” means a saturated or unsaturated monovalent monocyclicgroup of 4 to 8 ring atoms in which one or two ring atoms are heteroatomselected from N, O, or S(O)_(n), where n is an integer from 0 to 2, theremaining ring atoms being C, unless stated otherwise. Additionally, oneor two ring carbon atoms in the heterocyclyl ring can optionally bereplaced by a —CO— group. More specifically the term heterocyclylincludes, but is not limited to, pyrrolidino, piperidino,homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino,piperazino, tetrahydro-pyranyl, thiomorpholino, and the like. When theheterocyclyl ring is unsaturated it can contain one or two ring doublebonds provided that the ring is not aromatic. When the heterocyclylgroup contains at least one nitrogen atom, it is also referred to hereinas heterocycloamino and is a subset of the heterocyclyl group.

“Heterocyclylalkyl” or “heterocycloalkyl” means a -(alkylene)-R radicalwhere R is heterocyclyl ring as defined above e.g.,tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and thelike.

“Heterocyclylene” means a divalent heterocyclyl, as defined above,unless stated otherwise. When heterocyclene contains 4, 5, or 6 ringsatoms, it may be referred to herein as 4 to 6 membered heterocyclylene.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 10 ring atoms, unless otherwise stated, where one or more, (inone embodiment, one, two, or three), ring atoms are heteroatom selectedfrom N, O, or S, the remaining ring atoms being carbon. Representativeexamples include, but are not limited to, pyrrolyl, thienyl, thiazolyl,imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl,benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and thelike. As defined herein, the terms “heteroaryl” and “aryl” are mutuallyexclusive. When the heteroaryl ring contains 5- or 6 ring atoms it isalso referred to herein as 5- or 6-membered heteroaryl.

“Heteroarylene” means a divalent heteroaryl radical as defined above.

“Heteroaralkyl” means a -(alkylene)-R radical where R is heteroaryl asdefined above, e.g., pyridinylmethyl, and the like. When the heteroarylring in heteroaralkyl contains 5- or 6 ring atoms it is also referred toherein as 5-or 6-membered heteroaralkyl.

The phrase “R² and R⁹ are attached to the ring carbon atom that is metato the ring carbon attached to R¹” means the R² and R⁹ are located asindicated below:

The term “oxo,” as used herein, alone or in combination, refers to ═(O).

When needed, any definition herein may be used in combination with anyother definition to describe a composite structural group. Byconvention, the trailing element of any such definition is that whichattaches to the parent moiety. For example, the composite groupalkoxyalkyl means that an alkoxy group attached to the parent moleculethrough an alkyl group.

The present disclosure also includes protected derivatives of compoundsof Formula (IA) or (I). For example, when compounds of Formula (IA) or(I) contain groups such as hydroxy, carboxy, thiol or any groupcontaining a nitrogen atom(s), these groups can be protected withsuitable protecting groups. A comprehensive list of suitable protectivegroups can be found in T. W. Greene, Protective Groups in OrganicSynthesis, 5^(th) Ed., John Wiley & Sons, Inc. (2014), the disclosure ofwhich is incorporated herein by reference in its entirety. The protectedderivatives of compounds of the present disclosure can be prepared bymethods well known in the art.

The present disclosure also includes polymorphic forms of compounds ofFormula (IA) or (I) or a pharmaceutically acceptable salt thereof.Polymorphs are different crystalline forms of a compound that differ inarrangements of the molecules of that compound in a crystal lattice.Therefore, a single compound may give rise to a variety of polymorphicforms. The polymorphs of a compound usually have different meltingpoints, solubilities, densities and optical properties. Polymorphicforms of a compound can be distinguished by a number of techniques suchas X-ray diffractometry, IR or Raman spectroscopy.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds of Formula (IA) or (I) may also exist asprodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism:Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer,Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of thecompounds of Formula (IA) or (I) are structurally modified forms of thecompound that readily undergo chemical changes under physiologicalconditions to provide the active compound. Prodrugs are often usefulbecause, in some situations, they may be easier to administer than thecompound, or parent drug. They may, for instance, be bioavailable byoral administration whereas the parent drug is not. A wide variety ofprodrug derivatives are known in the art, such as those that rely onhydrolytic cleavage or oxidative activation of the prodrug. An example,without limitation, of a prodrug would be a compound which isadministered as an ester (the “prodrug”), but then is metabolicallyhydrolyzed to the carboxylic acid, the active entity. Additionalexamples include peptidyl derivatives of a compound of Formula (IA) or(I).

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as formic acid, acetic acid,propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; or

salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. It is understood that thepharmaceutically acceptable salts are non-toxic. Additional informationon suitable pharmaceutically acceptable salts can be found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, which is incorporated herein by reference in itsentirety.

The compounds of Formula (IA) or (I) may have asymmetric centers.Compounds of Formula (IA) or (I) containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.Individual stereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. All chiral, diastereomeric,all mixtures of chiral or diasteromeric forms, and racemic forms arewithin the scope of this disclosure, unless the specific stereochemistryor isomeric form is specifically indicated. It will also be understoodby a person of ordinary skill in the art that when a compound is denotedas (R) stereoisomer, it may contain the corresponding (S) stereoisomeras an impurity and vice versa.

Certain compounds of Formula (IA) or (I) can exist as tautomers and/orgeometric isomers. All possible tautomers and cis and trans isomers, asindividual forms and mixtures thereof are within the scope of thisdisclosure. Additionally, as used herein the term alkyl includes all thepossible isomeric forms of said alkyl group albeit only a few examplesare set forth. Furthermore, when the cyclic groups such as aryl,heteroaryl, heterocyclyl are substituted, they include all thepositional isomers albeit only a few examples are set forth.Furthermore, all hydrates of a compound of Formulae (IA) and (I) arewithin the scope of this disclosure.

The compounds of Formula (IA) or (I) may also contain unnatural amountsof isotopes at one or more of the atoms that constitute such compounds.Unnatural amounts of an isotope may be defined as ranging from theamount found in nature to an amount 100% of the atom in question. thatdiffer only in the presence of one or more isotopically enriched atoms.Exemplary isotopes that can be incorporated into a compound of Formula(IA) or (I) (and any embodiment thereof disclosed herein includingspecific compounds) include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H,³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl,¹²³I, and ¹²⁵I, respectively. Isotopically-labeled compounds (e.g.,those labeled with ³H and ¹⁴C) can be useful in compound or substratetissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e.,¹⁴C) isotopes can be useful for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements). In some embodiments, in compoundsdisclosed herein, including in Table 1 below one or more hydrogen atomsare replaced by ²H or ³H, or one or more carbon atoms are replaced by¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁵F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds can generally be prepared by following procedures analogous tothose disclosed in the Schemes or in the Examples herein, bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent.

Certain structures provided herein are drawn with one or more floatingsubstituents. Unless provided otherwise or otherwise clear from thecontext, the substituent(s) may be present on any atom of the ring towhich it is attached, where chemically feasible and valency rulespermitting. For example, in the structure:

the R⁷ substituent can replace any hydrogen on the benzo portion of thetricyclic ring, including the hydrogen of CH when X¹ is CH.

“Optionally substituted aryl” means aryl that is optionally substitutedwith one, two, or three substituents independently selected from alkyl,hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy,alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino, halo,haloalkyl, haloalkoxy, and cyano.

“Optionally substituted heteroaryl” means heteroaryl as defined abovethat is optionally substituted with one, two, or three substituentsindependently selected from alkyl, alkylthio, alkylsulfonyl, hydroxyl,cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl,haloalkoxy, amino, alkylamino, dialkylamino, and cyano.

“Optionally substituted heterocyclyl” means heterocyclyl as definedabove that is optionally substituted with one, two, or threesubstituents independently selected from alkyl, alkylthio,alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy,hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halo, haloalkyl,haloalkoxy, and cyano, unless stated otherwise.

“Optionally substituted heterocyclylene” is divalent optionallysubstituted heterocyclyl as defined above.

A “pharmaceutically acceptable carrier or excipient” means a carrier oran excipient that is useful in preparing a pharmaceutical compositionthat is generally safe, non-toxic and neither biologically nor otherwiseundesirable, and includes a carrier or an excipient that is acceptablefor veterinary use as well as human pharmaceutical use. “Apharmaceutically acceptable carrier/excipient” as used in thespecification and claims includes both one and more than one suchexcipient.

“Spirocycloalkyl” means a saturated bicyclic ring having 6 to 10 ringcarbon atoms wherein the rings are connected through only one atom, theconnecting atom is also called the spiroatom, most often a quaternarycarbon (“spiro carbon”). The spirocycloalkyl ring is optionallysubstituted with one or two substituents independently selected fromalkyl, halo, alkoxy, hydroxy, and cyano. Representative examplesinclude, but are not limited to, spiro[3.3]heptane, spiro[3.4]octane,spiro[3.5]nonane, spiro[4.4]nonane (1:2:1:1), and the like.

“Spiroheterocyclyl” means a saturated bicyclic ring having 6 to 10 ringatoms in which one, two, or three ring atoms are heteroatom selectedfrom N, O, or S(O)_(n), where n is an integer from 0 to 2, the remainingring atoms being C and the rings are connected through only one atom,the connecting atom is also called the spiroatom, most often aquaternary carbon (“spiro carbon”). The spiroheterocyclyl ring isoptionally substituted with one, two, or three substituentsindependently selected from alkyl, alkylthio, alkylsulfonyl, hydroxyl,cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, aminoalkyl, halo, haloalkyl, haloalkoxy, and cyano.Representative examples include, but are not limited to,2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane,2-azaspiro[3.4]octane, 2-azaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane,and the like.

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass ±10%, preferably ±5%, the recited value and the range isincluded.

The phrase “heteroaryl wherein the heteroaryl is optionally substitutedwith R^(d), R^(e), and R^(f) independently selected from hydrogen,alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and cyano” in thedefinition of R⁹ in Formula (I) (and similar phrases used to defineother groups in Formula (I)) is intended to cover heteroaryl that isunsubstituted and heteroaryl that is substituted with R^(d), R^(e), andR^(f).

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder,”“syndrome,” and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms, and causes the human or animal tohave a reduced duration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a disease or disorder described in thepresent disclosure. Such administration encompasses co-administration ofthese therapeutic agents in a substantially simultaneous manner, such asin a single capsule having a fixed ratio of active ingredients or inmultiple, separate capsules for each active ingredient. In addition,such administration also encompasses use of each type of therapeuticagent in a sequential manner. In either case, the treatment regimen willprovide beneficial effects of the drug combination in treating theconditions or disorders described herein.

The term “patient” is generally synonymous with the term “subject” andincludes all mammals including humans. Examples of patients includehumans, livestock such as cows, goats, sheep, pigs, and rabbits, andcompanion animals such as dogs, cats, rabbits, and horses. Preferably,the patient is a human.

“Treating” or “treatment” of a disease includes:

(1) preventing the disease, i.e. causing the clinical symptoms of thedisease not to develop in a mammal that may be exposed to or predisposedto the disease but does not yet experience or display symptoms of thedisease;

(2) inhibiting the disease, i.e., arresting or reducing the developmentof the disease or its clinical symptoms; or

(3) relieving the disease, i.e., causing regression of the disease orits clinical symptoms.

A “therapeutically effective amount” means the amount of a compound ofthe present disclosure or a pharmaceutically acceptable salt thereofthat, when administered to a patient for treating a disease, issufficient to affect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

The terms “inhibiting” and “reducing,” or any variation of these termsin relation of HIF-2α, includes any measurable decrease or completeinhibition to achieve a desired result. For example, there may be adecrease of about, at most about, or at least about 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 99%, or more, or any range derivable therein, reduction of HIF-2αactivity compared to normal.

EMBODIMENTS

In further embodiments 1-30 below, the present disclosure includes:

1A. In embodiment 1A, the compound of Formula (IA):

as described in the first aspect of the Summary above. In asubembodiment of embodiment 1A, R^(2a) and R^(9a) are independentlyhydrogen or deuterium.

1. In embodiment 1, the compound of Formula (I):

is as described in the first embodiment of the aspect in the Summaryabove.

In a first subembodiment of embodiment 1A or 1 or subembodiment withinembodiment 1A, the compound of Formula (IA) or (I), or a pharmaceuticalsalt thereof, is wherein R¹ is hydroxy.

In a second subembodiment of embodiment 1A or 1 or subembodiment withinembodiment 1A, the compound of Formula (IA) or (I), or a pharmaceuticalsalt thereof, is wherein R¹ is amino or halo, preferably R¹ is amino.

In a third subembodiment of embodiment 1A or 1 or subembodiment withinembodiment 1A, the compound of Formula (IA) or (I), or a pharmaceuticalsalt thereof, is wherein R¹ is —OCOR¹⁰, —OCOOR¹¹, —OCONR¹²R¹³,—OCHR¹⁴OCOR¹⁵ or —OCHR¹⁴OCOOR^(15a) where R¹⁰, R¹¹, R¹⁵, and R^(15a) areas defined in the Summary.

In a fourth subembodiment of embodiment 1A or 1 or subembodiment withinembodiment 1A, the compound of Formula (IA) or (I), or a pharmaceuticalsalt thereof, is wherein R¹ is —OP(O)(OH)₂, or —OCH₂OP(O)(OH)₂.

In a fifth subembodiment of embodiment 1A or 1 or subembodiment withinembodiment 1A, and subembodiments contained therein (i.e. first, second,third, and fourth subembodiments above), the compounds of Formula (IA)or (I), or a pharmaceutical salt thereof, are those wherein R⁶ is halo,preferably R⁶ is fluoro.

In a sixth subembodiment of embodiment 1A or 1 or subembodiment withinembodiment 1A, and subembodiments contained therein (i.e. first, second,third, and fourth subembodiments), the compounds of Formula (IA) or (I),or a pharmaceutical salt thereof, are those wherein R⁶ is alkyl,preferably R⁶ is methyl.

In a seventh subembodiment of embodiment 1A or 1 or subembodiment withinembodiment 1A, and subembodiments contained therein (i.e. first, second,third, and fourth subembodiments), the compounds of Formula (IA) (I), ora pharmaceutical salt thereof, are those wherein R⁶ is hydrogen ordeuterium.

In an eighth subembodiment of embodiment 1A or 1 or subembodiment withinembodiment 1A, and subembodiments contained therein (i.e. first, second,third, and fourth subembodiments), the compounds of Formula (1A) or (I),or a pharmaceutical salt thereof, are those wherein R⁶ is cycloalkyl,preferably R⁶ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In a ninth subembodiment of embodiment 1A or 1 or subembodiment withinembodiment 1A, and subembodiments contained therein (i.e. first, second,third, fourth, fifth, six, seventh, and eighth subembodiments above),the compounds of Formula (IA) or (I), or a pharmaceutical salt thereof,are those wherein R⁵ is halo or haloalkyl, preferably R⁵ isdifluoromethyl or trifluoromethyl.

In a tenth subembodiment of embodiment 1A or 1 or subembodiment withinembodiment 1A, and subembodiments contained therein (i.e. first, second,third, fourth, fifth, six, seventh, and eighth subembodiments above),the compounds of Formula (IA) or (I), or a pharmaceutical salt thereof,are those wherein R⁵ is alkyl, preferably R⁵ is methyl or ethyl.

In an eleventh subembodiment of embodiment 1A or 1 or subembodimentwithin embodiment 1A, and subembodiments contained therein (i.e. first,second, third, fourth, fifth, six, seventh, and eighth subembodiments),the compounds of Formula (IA) or (I), or a pharmaceutical salt thereof,are those wherein R⁵ is hydrogen or alkoxy.

In a twelfth subembodiment of embodiment 1A or 1 or subembodiment withinembodiment 1A, and subembodiments contained therein (i.e. first, second,third, and fourth subembodiments), the compounds of Formula (IA) or (I),or a pharmaceutical salt thereof, are those wherein R⁵ and R⁶ togetherwith the carbon to which they are attached form 3 to 6 memberedcycloalkylene, preferably R⁵ and R⁶ together with the carbon to whichthey are attached form cyclopropylene, cyclobutylene, or cyclopentyleneeach optionally substituted with one or two fluoro.

In a thirteenth subembodiment of embodiment 1A or 1 or subembodimentwithin embodiment 1A, and subembodiments contained therein (i.e. first,second, third, and fourth subembodiments), the compounds of Formula (IA)or (I), or a pharmaceutical salt thereof, are those wherein R⁵ and R⁶together with the carbon to which they are attached form 4 to 6 memberedoptionally substituted heterocyclylene, preferably R⁵ and R⁶ togetherwith the carbon to which they are attached form

In a fourteenth subembodiment of embodiment 1A or 1 or subembodimentwithin embodiment 1A, and subembodiments contained therein (i.e. firstto eleventh subembodiments), the compounds of Formula (IA) or (I), or apharmaceutical salt thereof, are those wherein R³ and R⁴ areindependently halo.

In a fifteenth subembodiment of embodiment 1A or 1 or subembodimentwithin embodiment 1A, and subembodiments contained therein (i.e. firstto eleventh subembodiments), the compounds of Formula (IA) or (I), or apharmaceutical salt thereof, are those wherein R³ is halo and R⁴ ishydrogen.

In a sixteenth subembodiment of embodiment 1A or 1 or subembodimentwithin embodiment 1A, and subembodiments contained therein (i.e. firstto fifteenth subembodiments), the compounds of Formula (IA) or (I), or apharmaceutical salt thereof, are those wherein X¹ is CH or CR⁷.

In a seventeenth subembodiment of embodiment 1A or 1 or subembodimentwithin embodiment 1A, and subembodiments contained therein (i.e. firstto fifteenth subembodiments), the compounds of Formula (IA) or (I), or apharmaceutical salt thereof, are those wherein X¹ is N.

2A. In embodiment 2A, the compound of embodiment 1A or apharmaceutically acceptable salt thereof, has the structure of formula(IIa1) or (IIb1):

In a first subembodiment of embodiment 2A the compound or subembodimentwithin embodiment 1A, or a pharmaceutically acceptable salt thereof, hasthe structure of formula (IIa1). In a second subembodiment of embodiment2A the compound or a pharmaceutically acceptable salt thereof, has thestructure of formula (IIb1).

2Aa. In embodiment 2Aa, the compound of embodiment 1A or subembodimentwithin embodiment 1A, or a pharmaceutically acceptable salt thereof, hasthe structure of formula (IIa1′) or (IIb1′)

In a first subembodiment of embodiment 2Aa the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIa1′). In a second subembodiment of embodiment 2Aa the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIb1′).

2. In embodiment 2, the compound of embodiment 1 or a pharmaceuticallyacceptable salt thereof, has the structure of formula (IIa) or (IIb):

In a first subembodiment of embodiment 2 the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIa). In a second subembodiment of embodiment 2 the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIb).

2a. In embodiment 2a, the compound of embodiment 1 or a pharmaceuticallyacceptable salt thereof, has the structure of formula (IIa′) or (IIb′):

In a first subembodiment of embodiment 2a the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIa′). In a second subembodiment of embodiment 2a the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIb′).

3A. In embodiment 3A, the compound of embodiment 1A or subembodimentwithin embodiment 1A, or a pharmaceutically acceptable salt thereof, hasthe structure of formula (IIIa1) or (IIIb1):

In a first subembodiment of embodiment 3A the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIIa1). In a second subembodiment of embodiment 3A the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIIb1).

3Aa. In embodiment 3Aa, the compound of embodiment 1A or apharmaceutically acceptable salt thereof, has the structure of formula(IIIa1′) or (IIIb1′):

In a first subembodiment of embodiment 3Aa the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIIa1′). In a second subembodiment of embodiment 3Aa the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIIb1′).

3. In embodiment 3, the compound of embodiment 1 or a pharmaceuticallyacceptable salt thereof, has the structure of formula (IIIa) or (IIIb):

In a first subembodiment of embodiment 3, wherein the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIIa). In a second subembodiment of embodiment 3, the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIIb).

3a. In embodiment 3a, the compound of embodiment 1 or a pharmaceuticallyacceptable salt thereof, has the structure of formula (IIIa′) or(IIIb′):

In a first subembodiment of embodiment 3a, the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIIa′). In a second subembodiment of embodiment 3a, the compound or apharmaceutically acceptable salt thereof, has the structure of formula(IIIb′).

4. In embodiment 4, the compound of embodiment 1 or a pharmaceuticallyacceptable salt thereof, has the structure of formula (IVa) or (IVb):

where R⁵ and R⁶ together with the carbon to which they are attached form3 to 6 membered cycloalkylene, preferably cyclopropylene, cyclobutyleneor cyclopentylene optionally substituted with one or two fluoro. In afirst subembodiment of embodiment 4, the compound or a pharmaceuticallyacceptable salt thereof, has the structure of formula (IVa). In a secondsubembodiment of embodiment 4, the compound or a pharmaceuticallyacceptable salt thereof, has the structure of formula (IVb).

5. In embodiment 5, the compound of embodiment 1 or a pharmaceuticallyacceptable salt thereof, has the structure of formula (Va) or (Vb):

where R⁵ and R⁶ together with the carbon to which they are attached form4 to 6 membered optionally substituted heterocyclylene, preferably R⁵and R⁶ together with the carbon to which they are attached form

In a first subembodiment of embodiment 5, the compound or apharmaceutically acceptable salt thereof, has the structure of formula(Va). In a second subembodiment of embodiment 5, the compound or apharmaceutically acceptable salt thereof, has the structure of formula(Vb).

6. In embodiment 6, the compound of embodiment 1 or a pharmaceuticallyacceptable salt thereof, has the structure of formula (VIa) or (VIb):

where R⁵ and R⁶ together with the carbon to which they are attached form3 to 6 membered cycloalkylene, preferably cyclopropylene, cyclobutyleneor cyclopentylene optionally substituted with one or two fluoro. In afirst subembodiment of embodiment 6, the compound or a pharmaceuticallyacceptable salt thereof, has the structure of formula (VIa). In a secondsubembodiment of embodiment 6, the compound or a pharmaceuticallyacceptable salt thereof, has the structure of formula (VIb).

7A. In embodiment 7A, the compound of embodiment 1A or apharmaceutically acceptable salt thereof, has the structure of formula(VIIa1) or (VIIb1):

In a first subembodiment of embodiment 7A the compound or apharmaceutically acceptable salt thereof, has the structure of formula(VIIa1). In a second subembodiment of embodiment 7A the compound or apharmaceutically acceptable salt thereof, has the structure of formula(VIIb1).

7. In embodiment 7, the compound of embodiment 1 or a pharmaceuticallyacceptable salt thereof, has the structure of formula (VIIa) or (VIIb):

In a first subembodiment of embodiment 7, the compound or apharmaceutically acceptable salt thereof, has the structure of formula(VIIa). In a second subembodiment of embodiment 7, the compound or apharmaceutically acceptable salt thereof, has the structure of formula(VIIb).

8. In embodiment 8, the compound of any one of embodiments 1A to 7 andsubembodiments contained therein (e.g., subembodiment within embodiment1A, subembodiments first to seventeenth of embodiment 1A and/or 1 andsubembodiments of embodiments 2A to 7) or a pharmaceutically acceptablesalt thereof, are where one of R³ and R⁴ is halo, preferably fluoro. Ina first subembodiment, R³ is fluoro and R⁴ is hydrogen.

9. In embodiment 9, the compound of any one of embodiments 1A to 7 andsubembodiments contained therein (e.g., subembodiment within embodiment1A, subembodiments first to seventeenth of embodiment 1A and/or 1 andsubembodiments of embodiments 2A to 7) or a pharmaceutically acceptablesalt thereof, are where R³ and R⁴ are halo, preferably R³ and R⁴ arefluoro.

10. In embodiment 10, the compound of any one of embodiments 1A to 9 andsubembodiments contained therein (e.g., subembodiment within embodiment1A, subembodiments first to seventeenth of embodiment 1A and/or 1 andsubembodiments of embodiments 2A to 9) or a pharmaceutically acceptablesalt thereof, is wherein L is O, S, SO, SO₂, or NH. In a firstsubembodiment of embodiment 10, L is O. In a second subembodiment ofembodiment 10, L is S. In a third subembodiment of embodiment 10, L isNH. In a fourth subembodiment of embodiment 10, L is SO or SO₂.

11. In embodiment 11, the compound of any one of embodiments 1A to 10and subembodiments contained therein (e.g., subembodiment withinembodiment 1A, subembodiments first to seventeenth of embodiment 1Aand/or 1 and subembodiments of embodiments 2A to 10) or apharmaceutically acceptable salt thereof, is wherein R⁸ is cycloalkyl,cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl,heterocyclylalkyl, heteroaryl, or heteroaralkyl wherein aryl orheteroaryl, each by itself or as part of aralkyl or heteroaralkyl, orheterocyclyl by itself or as part of heterocyclylalkyl is substitutedwith R^(a), R^(b), and R^(c) independently selected from hydrogen,alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, alkylidenyl,optionally substituted aryl, optionally substituted heteroaryl, andoptionally substituted heterocyclyl.

12A. In embodiment 12A, the compound of any one of embodiments 1A, 2A,2Aa, 3A, 3Aa, 7A, and 8 to 10 and subembodiments contained therein or apharmaceutically acceptable salt thereof, is wherein R⁸ is phenylsubstituted with R^(a), R^(b), R^(c), R^(g) and R^(h) wherein R^(a),R^(b), and R^(c) are independently selected from hydrogen, deuterium,alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl,optionally substituted heteroaryl, and optionally substitutedheterocyclyl and R^(g) and R^(h) are independently selected fromhydrogen, deuterium, and halo. In a first subembodiment of embodiment12A, R^(a), R^(b), and R^(c) are independently selected from hydrogen,deuterium, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, andcyano. In a second subembodiment of embodiment 12A, R^(a), R^(b), andR^(c) are independently selected from hydrogen, deuterium, methyl,methoxy, hydroxy, chloro, fluoro, cyano, difluoromethyl,trifluoromethyl, difluoromethoxy, and trifluoromethoxy and R^(g) andR^(h) are independently hydrogen or deuterium. In a third subembodimentof embodiment 12A, R⁸ is 3-chloro-5-fluorophenyl, 3,5-difluorophenyl,3-fluoro-5-methoxyphenyl, 3-cyano-5-fluorophenyl,3-chloro-5-cyanophenyl, 3-cyano-5-methylphenyl, 3-chloro-4-fluorophenyl,3-chloro-5-fluorophenyl, 3-fluoro-5-methylphenyl, 3-cyanophenyl,3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3-chloro-2-methylphenyl,3,5-dichlorophenyl, 3,5-dimethylphenyl, 2-chloro-6-methylphenyl,2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4-difluorophenyl,4-fluoro-3-methylphenyl, 3-cyano-4-fluorophenyl,3-cyano-5-difluoromethylphenyl or3-cyano-5-fluoro-2,4,6-trideuteriophenyl. In a fourth subembodiment ofembodiment 12A, R¹⁰ is 3-cyano-5-fluorophenyl or3-cyano-5-fluoro-2,4,6-trideuteriophenyl.

12. In embodiment 12, the compound of any one of embodiments 2, 2a, 3,3a to 6, and 7 to 10 and subembodiments contained therein (e.g.,subembodiments first to seventeenth of embodiment 1 and subembodimentsof embodiments 2,2a,3, 3^(a) to 6 and 7 to 10) or a pharmaceuticallyacceptable salt thereof, is wherein R⁸ is phenyl substituted with R^(a),R^(b), and R^(c) independently selected from hydrogen, alkyl, haloalkyl,haloalkyloxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl,aminoalkyl, optionally substituted aryl, optionally substitutedheteroaryl, and optionally substituted heterocyclyl. In a firstsubembodiment of embodiment 12, R^(a), R^(b), and R^(c) areindependently selected from hydrogen, alkyl, alkoxy, hydroxy, halo,haloalkyl, haloalkoxy, and cyano. In a second subembodiment ofembodiment 12, R^(a), R^(b), and R^(c) are independently selected fromhydrogen, methyl, methoxy, hydroxy, chloro, fluoro, cyano,difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.In a third subembodiment of embodiment 12, R⁸ is3-chloro-5-fluorophenyl, 3,5-difluorophenyl, 3-fluoro-5-methoxyphenyl,3-cyano-5-fluorophenyl, 3-chloro-5-cyanophenyl, 3-cyano-5-methylphenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl,3-fluoro-5-methylphenyl, 3-cyanophenyl, 3-trifluoromethylphenyl,3,4-dichlorophenyl, 3-chloro-2-methylphenyl, 3,5-dichlorophenyl,3,5-dimethylphenyl, 2-chloro-6-methylphenyl, 2,6-difluorophenyl,3,4,5-trifluorophenyl, 3,4-difluorophenyl, 4-fluoro-3-methylphenyl,3-cyano-4-fluorophenyl, or 3-cyano-5-difluoromethylphenyl. In a fourthsubembodiment of embodiment 12, R¹⁰ is 3-cyano-5-fluorophenyl.

13. In embodiment 13, the compound of any one of embodiments 1A to 10and subembodiments contained therein (e.g., subembodiment withinembodiment 1A, subembodiments first to seventeenth of embodiment 1Aand/or 1 and subembodiments of embodiments 2A to 10) or apharmaceutically acceptable salt thereof, is wherein R⁸ is cycloalkyl orcycloalkylalkyl each optionally substituted with one or two substituentsindependently selected from alkyl, halo, alkoxy, cyano, alkyldienyl,haloalkyldienyl, and hydroxy. In a first subembodiment of embodiment 13,R⁸ is cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl,cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, orcyclohexylmethyl, each optionally substituted with one or twosubstituents independently selected from alkyl, halo, alkoxy, cyano, andhydroxy. In a second subembodiment of embodiment 13, R⁶ iscyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl,cyclopentylmethyl, cyclopentylethyl, or cyclohexylmethyl, eachsubstituted with one or two substituents independently selected fromhydrogen, methyl, methoxy, cyano, and fluoro, preferably R⁸ iscyclopropylmethyl, 1-cyanocyclopropylmethyl, cyclobutylmethyl,2-fluorocyclopropylmethyl, or 1-cyanocyclobutylmethyl. In a thirdsubembodiment of embodiment 13, R⁸ is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl, each optionally substituted with one or twosubstituents independently selected from alkyl, halo, alkoxy, cyano, andhydroxy. In a fourth subembodiment of embodiment 13, R⁸ is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted withone or two substituents independently selected from methyl, cyano,methoxy, and fluoro, preferably, R⁸ is cyclobutyl, 3-fluorocyclobutyl,3,3-difluorocyclobutyl, 3-cyanocyclobutyl, 3-fluorocyclohexyl, or3-cyano-3-methylcyclobutyl.

14. In embodiment 14, the compound of any one of embodiments 1A to 10and subembodiments contained therein (e.g., subembodiment withinembodiment 1A, subembodiments first to seventeenth of embodiment 1Aand/or 1 and subembodiments of embodiments 2A to 10) or apharmaceutically acceptable salt thereof, is wherein R⁸ is heteroarylsubstituted with R^(a), R^(b), and R^(c) independently selected fromhydrogen, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl,optionally substituted heteroaryl, and optionally substitutedheterocyclyl. In a first subembodiment of embodiment 14, R⁸ is 5- or6-membered heteroaryl e.g., pyridyl, pyridazinyl, pyrimidinyl, thienyl,furanyl, thiazolyl, oxazolyl, imidazolyl, or pyrazinyl, each substitutedwith R^(a), R^(b), and R^(c) wherein R^(a) and R^(b) are independentlyselected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl,haloalkoxy, and cyano and R^(c) is selected from hydrogen, alkyl, halo,haloalkyl, and haloalkoxy. In a second subembodiment of embodiment 14,R⁸ is pyridin-3-yl, pyridin-2-yl, pyridazin-3-yl, pyridazin-4-yl,pyrimidin-5-yl, pyrimidin-2-yl, thien-2-yl, furan-2-yl, thiazol-5-yl,oxazol-5-yl, imidazol-5-yl, furan-3-yl thien-3-yl, thiazol-4-yl,pyridin-4-yl, oxazol-2-yl, imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl orthiazol-2-yl, each substituted with R^(a), R^(b), and R^(c) whereinR^(a) and R^(b) are independently selected from hydrogen, methyl,methoxy, hydroxy, chloro, fluoro, difluoromethyl, trifluoromethyl,difluoromethoxy, and trifluoromethoxy and R^(c) is selected fromhydrogen, methyl, cyano, chloro, fluoro, difluoromethyl,trifluoromethyl, difluoromethoxy, and trifluoromethoxy. In a thirdsubembodiment of embodiment 14, R⁸ is 5-cyanopyridin-3-yl,5-chloropyridin-3-yl, or 5-fluoropyridin-3-yl.

15. In embodiment 15, the compound of any one of embodiments 1A to 10and subembodiments contained therein (e.g., subembodiment withinembodiment 1A, subembodiments first to seventeenth of embodiment 1Aand/or 1 and subembodiments of embodiments 2A to 10) or apharmaceutically acceptable salt thereof, is wherein R⁸ is bicyclicheteroaryl substituted with R^(a), R^(b), and R^(c), wherein R^(a) andR^(b) are independently selected from hydrogen, alkyl, alkoxy, hydroxy,halo, haloalkyl, haloalkoxy, and cyano and R^(c) is selected fromhydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl,and aminoalkyl.

16. In embodiment 16, the compound of any one of embodiments 1A to 10and subembodiments contained therein (e.g., subembodiment withinembodiment 1A, subembodiments first to seventeenth of embodiment 1Aand/or 1 and subembodiments of embodiments 2A to 10) or apharmaceutically acceptable salt thereof, is wherein R⁸ is heterocyclyl,wherein heterocyclyl is substituted with R^(a), R^(b), and R^(c) whereinR^(a) and R^(b) are independently selected from hydrogen, alkyl, alkoxy,hydroxy, halo, haloalkyl, haloalkoxy, and cyano and R^(c) is hydrogen,alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, oraminoalkyl. In a first subembodiment of embodiment 18, R⁸ istetrahydrofuranyl, tetrahydropyranyl, or oxetanyl, each independentlysubstituted with R^(a) and R^(b) wherein R^(a) and R^(b) areindependently selected from hydrogen, methyl, and fluoro.

17. In embodiment 17, the compound of any one of embodiments 1A to 10and subembodiments contained therein (e.g., or subembodiment withinembodiment 1A, subembodiments first to seventeenth of embodiment 1Aand/or 1 and subembodiments of embodiments 2A to 10) or apharmaceutically acceptable salt thereof, is wherein R⁸ isspiroheterocyclyl. In one embodiment, the spiroheterocyclyl ringcontains at least one nitrogen atom. In a second embodiment, thespiroheterocyclyl ring contains at least one oxygen atom.

18. In embodiment 18, the compound of any one of embodiments 1A to 17and subembodiments contained therein (e.g., subembodiment withinembodiment 1A, subembodiments first to seventeenth of embodiment 1Aand/or 1 and subembodiments of embodiments 2A to 17) or apharmaceutically acceptable salt thereof, is wherein R⁷ is hydrogen,methyl, ethyl, methoxy, fluoro, trifluoromethyl or trifluoromethoxy. Ina first subembodiment, R⁷ is hydrogen.

19. In embodiment 19, the compound of any one of embodiments 1A to 18and subembodiments contained therein (e.g., subembodiment withinembodiment 1A, subembodiments first to seventeenth of embodiment 1Aand/or 1 and subembodiments of embodiments 2A to 18) or apharmaceutically acceptable salt thereof, is wherein R² is hydrogen,fluoro, methyl or ethyl. In a first subembodiment, R² is hydrogen. In afirst subembodiment, R² is methyl. In a third subembodiment, R² isfluoro.

20. In embodiment 20, the compound of any one of embodiments 1A to 19and subembodiments contained therein (e.g., subembodiment withinembodiment 1A, subembodiments first to seventeenth of embodiment 1Aand/or 1 and subembodiments of embodiments 2A to 19) or apharmaceutically acceptable salt thereof, is wherein R⁹ is hydrogen,alkyl, halo, hydroxy, or alkoxy. In a first subembodiment of embodiment20, R⁹ is hydrogen, methyl, methoxy, or fluoro.

21. In embodiment 21, the compound of any one of embodiments 1A to 20and subembodiments contained therein (e.g., subembodiment withinembodiment 1A, subembodiments first to seventeenth of embodiment 1Aand/or 1 and subembodiments of embodiments 2A to 20) or apharmaceutically acceptable salt thereof, is wherein R² and R⁹ areattached to the same carbon atom. In a first subembodiment of embodiment21, R² and R⁹ are attached to the ring carbon atom that is meta to thering carbon attached to R¹.

22A. In embodiment 22A, the compound of any one of embodiments 1A, 2A,2Aa, 3A, 3Aa, 7A, 8 to 10, 12A and 13 to 18 and subembodiments containedtherein or a pharmaceutically acceptable salt thereof, is wherein R² andR⁹ are attached to the ring carbon atom that is meta to the ring carbonattached to R¹ and wherein R² is hydrogen or deuterium and R⁹ ishydrogen, methyl, or fluoro.

22B. In embodiment 22B, the compound of embodiment 22A andsubembodiments contained therein or a pharmaceutically acceptable saltthereof, is wherein R² is hydrogen or deuterium and R⁹ is fluoro.

22C. In embodiment 22C, the compound of embodiment 22A and 22B andsubemodiments contained therein or a pharmaceutically acceptable saltthereof, is wherein R^(2a) and R^(9a) are independently hydrogen,deuterium, or fluoro, preferably hydrogen or fluoro, more preferablyhydrogen.

22. In embodiment 22, the compound of any one of embodiments 1A to 18and 22C and subembodiments contained therein or a pharmaceuticallyacceptable salt thereof, is wherein R² and R⁹ are attached to the samecarbon atom and together with the carbon atom to which they are attachedform oxo. In a first subembodiment of embodiment 22, R² and R⁹ areattached to the ring carbon atom that is meta to the ring carbonattached to R¹.

23. In embodiment 23, the compound of any one of embodiments 1A to 18and 22C and subembodiments contained therein or a pharmaceuticallyacceptable salt thereof, is wherein R² and R⁹ are attached to the samecarbon atom and together with the carbon atom to which they are attachedform 3 to 6 membered cycloalkylene. In a first subembodiment ofembodiment 23, R² and R⁹ are attached to the same carbon atom andtogether with the carbon atom to which they are attached formcycloproplene. In a first subembodiment of embodiment 23, R² and R⁹ areattached to the ring carbon atom that is meta to the ring carbonattached to R¹.

24. In embodiment 24, the compound of any one of embodiments 1A to 18and 22C and subembodiments contained therein or a pharmaceuticallyacceptable salt thereof, is wherein R² and R⁹ are attached to the samecarbon atom and together with the carbon atom to which they are attachedform 4 to six membered heterocyclylene. In a first subembodiment ofembodiment 23, R² and R⁹ are attached to the same carbon atom andtogether with the carbon atom to which they are attached formoxetan-4-yl. In a first subembodiment of embodiment 24, R² and R⁹ areattached to the ring carbon atom that is meta to the ring carbonattached to R¹.

25. In embodiment 25, the compound of any one of embodiments 1A to 18and subembodiments contained therein or a pharmaceutically acceptablesalt thereof, is wherein R² and R⁹ are attached to the same carbon atomand together with the carbon atom to which they are attached formalkyldienyl, preferably vinydienyl. In a first subembodiment ofembodiment 22, R² and R⁹ are attached to the ring carbon atom that ismeta to the ring carbon attached to R¹.

26. In embodiment 26, the compound of any one of embodiments 1A, 2A,2Aa, 12A, 13 to 20 and subembodiments contained therein or apharmaceutically acceptable salt thereof is a compound of formula(VIIIa1) or (VIIIb1):

In one embodiment the compound has formula (VIIIb1).

27. In embodiment 27, the compound of embodiment 26 and subembodimentcontained therein or a pharmaceutically acceptable salt thereof iswherein R² is hydrogen or deuterium and R⁹ is hydrogen, fluoro, ormethyl, preferably fluoro, and R^(2a) and R^(9a) are independentlyhydrogen, deuterium, or fluoro. In a first subembodiment of embodiment26, R^(2a) and R^(9a) are independently hydrogen or deuterium. In asecond subembodiment of embodiment 26, R^(2a) and R^(9a) areindependently hydrogen or fluoro.

28. In embodiment 28, the compound of any one of embodiments 1, 2, 2a,and 12 to 20 and subembodiments contained therein or a pharmaceuticallyacceptable salt thereof is a compound of formula (VIIIa) or (VIIIb):

In one embodiment the compound has formula (VIIIb).

29. In embodiment 29, the compound of embodiment 28 and subembodimentcontained therein or a pharmaceutically acceptable salt thereof iswherein R² is hydrogen and R⁹ is hydrogen, fluoro, or methyl.

30. In embodiment 30, the compound of any one of embodiments 26 to 29and subembodiment contained therein or a pharmaceutically acceptablesalt thereof is wherein R⁷ is hydrogen and R⁸ is 3-cyano-5-fluorophenylor 3-cyano-5-fluoro-2,4,6-trideuteriophenyl.

It is understood that the embodiments and subembodiments set forth aboveinclude all combination of embodiments and subembodiments listedtherein. For example, R⁹ listed in seventh sub-embodiment of embodiment20, can independently be combined with one or more of the embodiments1A-30 and/or subembodiments contained therein.

In further embodiment 40 to 99, the present disclosure includes:

40. A compound of Formula (IA):

wherein:

X¹ is CH or N;

R¹ is hydroxy, halo, amino, —OP(O)(OH)₂, —OCH₂OP(O)(OH)₂, —OCOR¹⁰,—OCOOR¹¹, —OCONR¹²R¹³, —OCHR¹⁴OCOR¹⁵ or —OCHR¹⁴OCOOR^(15a) where R¹⁰,R¹¹, and R¹⁵ and R^(15a) are independently alkyl or alkyl substitutedwith amino, carboxy or hydroxy, R¹² and R¹³ are independently hydrogen,alkyl, or alkyl substituted with amino, carboxy or hydroxy or R¹² andR¹³ together with the nitrogen atom to which they are attached formoptionally substituted heterocyclyl, and each R¹⁴ is hydrogen, alkyl, orhaloalkyl;

R² is hydrogen, deuterium, alkyl, halo, haloalkyl, alkenyl, or alkynyl;

R^(2a) is hydrogen or deuterium;

R³ and R⁴ are independently hydrogen, deuterium, alkyl, cycloalkyl,halo, haloalkyl, hydroxyalkyl, or alkoxyalkyl; or

R³ and R⁴ together with the carbon to which they are attached form oxo,3 to 6 membered cycloalkylene, or 4 to 6 membered optionally substitutedheterocyclylene;

R⁵ is hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxy, or alkoxy;

R⁶ is hydrogen, deuterium, alkyl, cycloalkyl, or halo; or

R⁵ and R⁶ together with the carbon to which they are attached form oxo,alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to 6 memberedoptionally substituted heterocyclylene; provided R⁵ and R⁶ and R³ and R⁴together with the carbon to which they are attached do not form oxo,cycloalkylene or optionally substituted 4 to 6 membered heterocyclylenesimultaneously;

R⁷ is hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, orhaloalkoxy;

L is a bond, S, SO, SO₂, O, CO, or NR¹⁶ where R¹⁶ is hydrogen or alkyl;

R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl,spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkylwherein aryl or heteroaryl, each by itself or as part of aralkyl orheteroaralkyl, or heterocyclyl by itself or as part of heterocyclylalkylis substituted with R^(a), R^(b), R^(c), R^(g) and/or R^(h) whereinR^(a), R^(b), and R^(c) are independently selected from hydrogen,deuterium, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, alkylidenyl,optionally substituted aryl, optionally substituted heteroaryl, andoptionally substituted heterocyclyl and R^(g) and R^(h) areindependently selected from hydrogen, deuterium, and halo; and

R⁹ is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo,haloalkyl, haloalkoxy, alkylsulfoxide, alkylsulfonyl, or heteroarylwherein the heteroaryl is optionally substituted with R^(d), R^(e), andR^(f) independently selected from hydrogen, alkyl, haloalkyl,haloalkoxy, alkoxy, hydroxy, halo, and cyano; or

when R⁹ and R² are attached to the same carbon atom, they can combine toform oxo, alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to 6-memberedheterocyclylene;

R^(9a) is hydrogen or deuterium;

a pharmaceutically acceptable salt thereof.

41. A compound of Formula (I):

wherein:

X¹ is CH or N;

R¹ is hydroxy, halo, amino, —OP(O)(OH)₂, —OCH₂OP(O)(OH)₂, —OCOR¹⁰,—OCOOR¹¹, —OCONR¹²R¹³, —OCHR¹⁴OCOR¹⁵ or —OCHR¹⁴OCOOR^(15a) where R¹⁰,R¹¹, R¹⁵, and R^(15a) are independently alkyl or alkyl substituted withamino, carboxy or hydroxy, R¹² and R¹³ are independently hydrogen,alkyl, or alkyl substituted with amino, carboxy or hydroxy or R¹² andR¹³ together with the nitrogen atom to which they are attached formoptionally substituted heterocyclyl, and each R¹⁴ is hydrogen, alkyl, orhaloalkyl;

R² is hydrogen, deuterium, alkyl, haloalkyl, alkynyl, or alkenyl;

R³ and R⁴ are independently hydrogen, deuterium, alkyl, cycloalkyl,halo, haloalkyl, hydroxyalkyl, or alkoxyalkyl; or

R³ and R⁴ together with the carbon to which they are attached form oxo,3 to 6 membered cycloalkylene, or 4 to 6 membered optionally substitutedheterocyclylene;

R⁵ is hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxy, or alkoxy;

R⁶ is hydrogen, deuterium, alkyl, cycloalkyl, or halo; or

R⁵ and R⁶ together with the carbon to which they are attached form 3 to6 membered cycloalkylene or 4 to 6 membered optionally substitutedheterocyclylene; provided R⁵ and R⁶ and R³ and R⁴ together with thecarbon to which they are attached do not form cycloalkylene oroptionally substituted 4 to 6 membered heterocyclylene simultaneously;

R⁷ is hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, orhaloalkoxy;

L is a bond, S, SO, SO₂, O, CO, or NR¹⁶ where R¹⁶ is hydrogen or alkyl;

R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl,spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkylwherein aryl or heteroaryl, each by itself or as part of aralkyl orheteroaralkyl, or heterocyclyl by itself or as part of heterocyclylalkylis substituted with R^(a), R^(b), and/or R^(c) independently selectedfrom hydrogen, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo,cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl,alkylidenyl, optionally substituted aryl, optionally substitutedheteroaryl, and optionally substituted heterocyclyl; and

R⁹ is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo,haloalkyl, haloalkoxy, alkylsulfoxide, or alkylsulfonyl, or heteroarylwherein the heteroaryl is optionally substituted with R^(d), R^(e), andR^(f) independently selected from hydrogen, alkyl, haloalkyl,haloalkoxy, alkoxy, hydroxy, halo, and cyano; or

when R⁹ and R² are attached to the same carbon atom, they can combine toform oxo, alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to 6-memberedheterocyclylene;

a pharmaceutically acceptable salt thereof.

42. The compound of embodiment 40 or 41, or a pharmaceuticallyacceptable salt thereof, wherein R³ and R⁴ are independently halo.

43. The compound of embodiment 40 or 41, or a pharmaceuticallyacceptable salt thereof, wherein R³ is halo and R⁴ is hydrogen.

44. The compound of embodiment 40, 41, 42, or 43, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is hydroxy.

45. The compound of embodiment 40, 41, 42, or 43, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is amino.

46. The compound of any one of embodiments 40 to 45, or apharmaceutically acceptable salt thereof, wherein R⁶ is halo.

47. The compound of any one of embodiments 40 to 45, or apharmaceutically acceptable salt thereof, wherein R⁶ is alkyl,preferably R⁶ is methyl.

48. The compound of any one of embodiments 40 to 45, or apharmaceutically acceptable salt thereof, wherein R⁶ is hydrogen.

49. The compound of any one of embodiments 40 to 45, or apharmaceutically acceptable salt thereof, wherein R⁶ is cycloalkyl,preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

50. The compound of any one of embodiments 40 to 49, or apharmaceutically acceptable salt thereof, wherein R⁵ is halo, preferablyfluoro.

51. The compound of any one of embodiments 40 to 49, or apharmaceutically acceptable salt thereof, wherein R⁵ is haloalkyl,preferably R⁵ is difluoromethyl or trifluoromethyl.

52. The compound of any one of embodiments 40 to 49, or apharmaceutically acceptable salt thereof, wherein R⁵ is alkyl,preferably R⁵ is methyl or ethyl.

53. The compound of any one of embodiments 40 to 49, or apharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen oralkoxy.

54. The compound of any one of embodiments 40 to 45, or apharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ togetherwith the carbon to which they are attached form 3 to 6 memberedcycloalkylene, preferably cyclopropylene, cyclobutylene orcyclopentylene optionally substituted with one or two fluoro.

55. The compound of any one of embodiments 40 to 54, or apharmaceutically acceptable salt thereof, wherein X¹ is CR⁷.

56. The compound of embodiment 40 or a pharmaceutically pharmaceuticallyacceptable salt thereof, having the structure of formula (IIa1) or(IIb1):

57. The compound of embodiment 40 or a pharmaceutically acceptable saltthereof, having the structure of formula (IIa1′) or (IIb1′):

58. The compound of embodiment 41, or a pharmaceutically acceptable saltthereof, having the structure of formula (IIa) or (IIb):

59. The compound of embodiment 41, or a pharmaceutically acceptable saltthereof, having the structure of formula (IIa′) or (IIb′).

60. The compound of embodiment 41, or a pharmaceutically acceptable saltthereof, having the structure of formula (IVa):

where R⁵ and R⁶ together with the carbon to which they are attached form3 to 6 membered cycloalkylene, preferably cyclopropylene, cyclobutyleneor cyclopentylene optionally substituted with one or two fluoro.

61. The compound of embodiment 41, or a pharmaceutically acceptable saltthereof, having the structure of formula (VIa) or (VIb):

where R⁵ and R⁶ together with the carbon to which they are attached form3 to 6 membered cycloalkylene, preferably cyclopropylene, cyclobutyleneor cyclopentylene optionally substituted with one or two fluoro.

62. The compound of embodiment 41, or a pharmaceutically acceptable saltthereof, having the structure of formula (VIIa) or (VIIb):

63. The compound of any one of embodiments 40 to 62, or apharmaceutically acceptable salt thereof, wherein R³ is fluoro.

64. The compound of any one of embodiments 40-42 and 44 to 62, or apharmaceutically acceptable salt thereof, where R³ and R⁴ are fluoro.

65. The compound of any one of embodiments 40 to 64, or apharmaceutically acceptable salt thereof, wherein L is O, S, SO, SO₂, orNH.

66. The compound of embodiment 65, or a pharmaceutically acceptable saltthereof, wherein L is O.

67. The compound of any one of embodiments 40 to 66, or apharmaceutically acceptable salt thereof, wherein R⁸ is cycloalkyl,cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl,heterocyclylalkyl, heteroaryl, or heteroaralkyl wherein aryl orheteroaryl, each by itself or as part of aralkyl or heteroaralkyl, orheterocyclyl by itself or as part of heterocyclylalkyl is substitutedwith R^(a), R^(b), and R^(c) independently selected from hydrogen,alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, alkylidenyl,optionally substituted aryl, optionally substituted heteroaryl, andoptionally substituted heterocyclyl.

68. The compound of any one of embodiments 40, 42 to 57, and 63 to 66and subembodiments contained therein, or a pharmaceutically acceptablesalt thereof, is wherein R⁸ is phenyl substituted with R^(a), R^(b),R^(c), R^(g) and R^(h) wherein R^(a), R^(b), and R^(c) are independentlyselected from hydrogen, deuterium, alkyl, haloalkyl, haloalkyloxy,alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl,optionally substituted aryl, optionally substituted heteroaryl, andoptionally substituted heterocyclyl and R^(g) and R^(h) areindependently selected from hydrogen, and halo.

68A. The compound of any one of embodiments 40, 42 to 57, and 63 to 66and subembodiments contained therein, or a pharmaceutically acceptablesalt thereof, is wherein R⁸ is 3-chloro-5-fluorophenyl,3,5-difluorophenyl, 3-fluoro-5-methoxyphenyl, 3-cyano-5-fluorophenyl,3-chloro-5-cyanophenyl, 3-cyano-5-methylphenyl, 3-chloro-4-fluorophenyl,3-chloro-5-fluorophenyl, 3-fluoro-5-methylphenyl, 3-cyanophenyl,3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3-chloro-2-methylphenyl,3,5-dichlorophenyl, 3,5-dimethylphenyl, 2-chloro-6-methylphenyl,2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4-difluorophenyl,4-fluoro-3-methylphenyl, 3-cyano-4-fluorophenyl,3-cyano-5-difluoromethylphenyl or3-cyano-5-fluoro-2,4,6-trideuteriophenyl. In a first subembodiment ofembodiment 68A, R¹⁰ is 3-cyano-5-fluorophenyl or3-cyano-5-fluoro-2,4,6-trideuteriophenyl

69. The compound of any one of embodiments 41 to 55 and 58 to 66, or apharmaceutically acceptable salt, thereof, wherein R⁸ is phenylsubstituted with R^(a), R^(b), and R^(c) independently selected fromhydrogen, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl,optionally substituted heteroaryl, and optionally substitutedheterocyclyl.

70. The compound of any one of embodiments 41 to 55 and 58 to 66, or apharmaceutically acceptable salt thereof, wherein R⁸ is3-chloro-5-fluorophenyl, 3,5-difluorophenyl, 3-fluoro-5-methoxyphenyl,3-cyano-5-fluorophenyl, 3-chloro-5-cyanophenyl, 3-cyano-5-methylphenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl,3-fluoro-5-methylphenyl, 3-cyanophenyl, 3-trifluoromethylphenyl,3,4-dichlorophenyl, 3-chloro-2-methylphenyl, 3,5-dichlorophenyl,3,5-dimethylphenyl, 2-chloro-6-methylphenyl, 2,6-difluorophenyl,3,4,5-trifluorophenyl, 3,4-difluorophenyl, 4-fluoro-3-methylphenyl,3-cyano-4-fluorophenyl, or 3-cyano-5-difluoromethylphenyl. In a fourthsubembodiment of embodiment 26, R¹⁰ is 3-cyano-5-fluorophenyl.

71. The compound of any one of embodiments 40 to 66 and anysubembodiments contained therein, or a pharmaceutically acceptable saltthereof, wherein R⁸ is cycloalkyl or cycloalkylalkyl each optionallysubstituted with one or two substituents independently selected fromalkyl, halo, alkoxy, cyano, and hydroxy.

72. The compound of any one of embodiments 40 to 66 and anysubembodiments contained therein, or a pharmaceutically acceptable saltthereof, wherein R⁸ is heteroaryl substituted with R^(a), R^(b), andR^(c) independently selected from hydrogen, alkyl, haloalkyl,haloalkyloxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl,aminoalkyl, optionally substituted aryl, optionally substitutedheteroaryl, and optionally substituted heterocyclyl.

73. The compound of any one of embodiments 40 to 66, or apharmaceutically acceptable salt, thereof, wherein R⁸ is 5- or6-membered heteroaryl (e.g., pyridyl, pyridazinyl, pyrimidinyl, thienyl,furanyl, thiazolyl, oxazolyl, imidazolyl, or pyrazinyl), eachsubstituted with R^(a), R^(b), and R^(c) wherein R^(a) and R^(b) areindependently selected from hydrogen, alkyl, alkoxy, hydroxy, halo,haloalkyl, haloalkoxy, and cyano and R^(c) is selected from hydrogen,alkyl, halo, haloalkyl, and haloalkoxy.

74. The compound of any one of embodiments 40 to 66, or apharmaceutically acceptable salt, thereof, wherein R⁸ is pyridin-3-yl,pyridin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-5-yl,pyrimidin-2-yl, thien-2-yl, furan-2-yl, thiazol-5-yl, oxazol-5-yl,imidazol-5-yl, furan-3-yl thien-3-yl, thiazol-4-yl, pyridin-4-yl,oxazol-2-yl, imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl, or thiazol-2-yl,and is substituted with R^(a), R^(b), and R^(c) wherein R^(a) and R^(b)are independently selected from hydrogen, methyl, methoxy, hydroxy,chloro, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, andtrifluoromethoxy and R^(c) is selected from hydrogen, methyl, cyano,chloro, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, andtrifluoromethoxy.

75. The compound of embodiment 74, or a pharmaceutically acceptable saltthereof, wherein R⁸ is 5-cyanopyridin-3-yl, 5-chloropyridin-3-yl, or5-fluoropyridin-3-yl.

76. The compound of any one of embodiments 40 to 75, or apharmaceutically acceptable salt thereof, wherein R⁷ is hydrogen,methyl, ethyl, methoxy, fluoro, trifluoromethyl, or trifluoromethoxy,preferably R⁷ is hydrogen.

77. The compound of any one of embodiments 40 to 76, or apharmaceutically acceptable salt thereof, wherein R² is hydrogen,fluoro, methyl or ethyl.

78. The compound of any one of embodiments 40 to 77, or apharmaceutically acceptable salt thereof, wherein R⁹ is hydrogen, alkyl,halo, hydroxy, or alkoxy.

79. The compound of any one of embodiments 40 to 77, or apharmaceutically acceptable salt thereof, wherein R⁹ is hydrogen,methyl, methoxy, or fluoro.

80. The compound of any one of embodiments 40 to 79, or apharmaceutically acceptable salt thereof, wherein R² and R⁹ are attachedto the same carbon atom.

81. The compound of embodiment 80, or a pharmaceutically acceptable saltthereof, wherein R² and R⁹ are attached to the ring carbon atom that ismeta to the ring carbon attached to R¹.

82. The compound of any one of embodiments 40 to 76, or apharmaceutically acceptable salt thereof, wherein R² and R⁹ are attachedto the same carbon atom and together with the carbon atom to which theyare attached form oxo.

83. The compound of any one of embodiments 40 to 76, or apharmaceutically acceptable salt thereof, wherein R² and R⁹ are attachedto the same carbon atom and together with the carbon atom to which theyare attached form 3 to 6 membered cycloalkylene.

84. The compound of embodiment 83, or a pharmaceutically acceptable saltthereof, wherein R² and R⁹ together with the carbon atom to which theyare attached form cycloproplene.

85. The compound of any one of embodiments 40 to 76, or apharmaceutically acceptable salt thereof, wherein R² and R⁹ are attachedto the same carbon atom and together with the carbon atom to which theyare attached form 4 to six membered heterocyclylene.

85a. The compound of any one of embodiments 40 to 76, or apharmaceutically acceptable salt thereof, wherein R² and R⁹ are attachedto the same carbon atom and together with the carbon atom to which theyare attached form alkyldienyl, preferably vinydienyl.

86. The compound of any one of embodiments 82 to 85a, or apharmaceutically acceptable salt thereof, wherein R² and R⁹ are attachedto the ring carbon atom that is meta to the ring carbon attached to R¹.

87. The compound of any one of embodiments 40, 42 to 57, 63 to 68A and71 to 76, or a pharmaceutically acceptable salt thereof, is wherein R²and R⁹ are attached to the ring carbon atom that is meta to the ringcarbon attached to R¹ and wherein R² is hydrogen or deuterium and R⁹ ishydrogen, methyl, or fluoro.

88. The compound of embodiment 87 and subembodiments contained thereinor a pharmaceutically acceptable salt thereof, is wherein R² is hydrogenor deuterium and R⁹ is fluoro.

89. The compound of any one of embodiments 40, 65 to 68A, and 71 to 79or a pharmaceutically acceptable salt thereof having the structure offormula (VIIIa1) or (VIIIb1):

preferably the structure of formula (VIIIb1).

90. The compound of embodiment 89, or a pharmaceutically acceptable saltthereof, wherein R^(2a) and R^(9a) are independently hydrogen ordeuterium, preferably R^(2a) and R^(9a) are hydrogen.

91. The compound of any one of embodiments 41, 65 to 67, and 69 to 79,or a pharmaceutically acceptable salt thereof, having the structure offormula (VIIIa) or (VIIIb):

preferably the structure of formula (VIIIb).

92. The compound of embodiment 91, or a pharmaceutically acceptable saltthereof, wherein R² is hydrogen and R⁹ is hydrogen, fluoro, or methyl.

93. A pharmaceutical composition comprising a compound of any one ofembodiments 40-92, or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable excipient.

94. A method of inhibiting HIF2α which method comprises contacting HIF2αwith a compound of any one of embodiments 40-92, or a pharmaceuticallyacceptable salt thereof, or with a pharmaceutical composition ofembodiment 93.

95. A method of treating a disease mediate by HIF2α in a patient whichmethod comprises administering to the patient in recognized needthereof, a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of any one of embodiments 40-92, or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable excipient.

96. A method of treating cancer in a patient which method comprisesadministering to the patient in recognized need thereof, atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of any one of embodiments 40-92, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

97. The method of embodiment 96, wherein the compound of embodiment40-92 or a pharmaceutically acceptable salt thereof, can be optionallyadministered in combination with at least one other anticancer agent.

98. The method of embodiment 96 or 97, wherein the cancer is renalcancer or glioblastoma.

99. The method of embodiment 95, wherein the disease is NASH, pulmonaryartery hypertension, or inflammatory bowel disease.

Representative compounds of the disclosure made are disclosed inCompound Table I below:

TABLE I Compound # Structure Name  1

3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile  2

3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7- yl)oxy)benzonitrile  3

3-fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7- yl)oxy)benzonitrile  4

3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7- yl)oxy)benzonitrile  5

3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile  6

3-fluoro-5-(((1R,2aS)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile  7

3-fluoro-5-(((1R,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile  8

1,3,3,4,4-pentafluoro-7-((5-fluoropyridin-3-yl)oxy)-1,2,3,4-tetrahydro-2aH- cyclopenta[cd]inden-2a-ol  9

3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydrospiro[cyclopenta[cd]indene-1,1′-cyclopropan]-7-yl)oxy)benzonitrile 10

3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methyl-2,2a,3,4-tetrahydro-1H- cyclopenta[cd]inden-7-yl)oxy)benzonitrile11

3-fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-1-methyl-2,2a,3,4-tetrahydro-1H- cyclopenta[cd]inden-7-yl)oxy)benzonitrile12

3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-1-methyl-2,2a,3,4-tetrahydro-1H- cyclopenta[cd]inden-7-yl)oxy)benzonitrile13

3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7- yl)oxy)benzonitrile 14

3-((2a-amino-1,3,3,4,4-pentafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5- fluorobenzonitrile 15

3-fluoro-5-((1,1,2a,3,3,4,4-heptafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7- yl)oxy)benzonitrile 16

3-((3,3-difluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5- fluorobenzonitrile 17

3-((3,3-difluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5- fluorobenzonitrile 18

3-((3,3-difluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5- fluorobenzonitrile 19

3-fluoro-5-((1,3,3-trifluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5- yl)oxy)benzonitrile 20

3-fluoro-5-((1,2,2,3,3,4,4-heptafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7- yl)oxy)benzonitrile 21

3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H- cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)benzonitrile 22

3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)oxy)benzonitrile- 2,4,6-d3 23a

(R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile 23b

(S)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile 24a

3-fluoro-5-(((2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile 24b

3-fluoro-5-(((2R,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrileAdditional representative compounds of Formula (I) that can be preparedare shown in Table II below:

Compound # Structure II-1

II-4

II-5

II-6

II-7

II-8

II-10

II-11

II-12

II-13

II-14

II-15

II-16

General Synthetic Scheme

Compounds of this disclosure can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis,Mo.) or are prepared by methods known to those skilled in the artfollowing procedures set forth in references such as Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition) and Larock's ComprehensiveOrganic Transformations (VCH Publishers Inc., 1989). These schemes aremerely illustrative of some methods by which the compounds of thisdisclosure can be synthesized, and various modifications to theseschemes can be made and will be suggested to one skilled in the artreading this disclosure. The starting materials and the intermediates,and the final products of the reaction may be isolated and purified ifdesired using conventional techniques, including but not limited tofiltration, distillation, crystallization, chromatography and the like.Such materials may be characterized using conventional means, includingphysical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure over a temperature range from about −78°C. to about 150° C., such as from about 0° C. to about 125° C. andfurther such as at about room (or ambient) temperature, e.g., about 20°C.

Compounds of Formula (I) where X¹ is CH, R¹ is hydroxyl, R³, R⁴, R⁵, R⁶,R⁷, and R⁸ are as defined in the Summary (or any embodiments thereof),and R⁹ and R² are combined to form alkyldienyl, can be prepared asillustrated and described in Scheme 1 below.

Reformastky reaction between an aldehyde of formula 1-a where R⁷ is asdescribed in the Summary or a precursor group thereof and a compound offormula 1-b where X¹ is halide and R³ is as defined, e.g., independentlyhydrogen, deuterium, alkyl, halo, haloalkyl, hydroxyalkyl, oralkoxyalkyl, mediated by zinc metal provides a compound of formula 1-c.Compounds of formula 1-a and 1-b are commercially available or they canbe prepared by methods well known in the art. For example,2-bromo-4-fluorobenzaldehyde, ethyl 2-bromo-2,2-difluoroacetate, ethyl2-bromo-2-methylpropanoate, ethyl 2-bromopropanoate, ethyl2-bromoacetate are commercially available. The hydroxyl group in 1-c canbe oxidized under oxidative conditions such as 2-iodoxybenzoic acid(IBX) or TPAP, NMO to give a ketone of formula 1-d. The keto group incompound of formula 1-d can be functionalized to provide compound offormula 1-e where R⁵ and R⁶ are as described in the Summary by methodswell known in the art. For example, a compound of formula 1-e where R⁵and R⁶ are fluoro can be synthesized from 1-d by treatment with afluorinating agent such as DAST or SF₄ under conditions well known inthe art. Cyclization of 1-e can be achieved by treating it with alkyllithium reagent such n-BuLi to give ketone 1-f. The carbonyl group in1-f can be reduced with reducing reagents such as NaBH₄ to providealcohol 1-g.

Compounds of formula 1-g can be converted to compounds of formula 1-h bylithiation of 1-g, followed by treating the lithio intermediate withCBr₄. Oxidation of 1-h with oxidative reagents such as IBX providesketone of formula 1-i. Addition of allyl metal reagent such as allylmagnesium bromide to compounds of formula 1-i provides compounds offormula 1-j.

Alternatively, compound of formula 1-j can be prepared from 1-f byaddition of allyl metal reagent such as allyl magnesium bromide tocompounds of formula 1-f illustrated below:

Lithiation of 1-g with bases such LDA followed by treating the lithiointermediate with bromination reagent such as CBr₄ or1,2-dibromotetrafluoroethane provides compound of formula 1-j. Ifdesired, enantioselective synthesis of compounds of formula 1-g can beachieved by addition of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneto compounds of formula 1-f in the presence of a ligand such as 1-m anda suitable base such as tBuONa in organic solvents such as MeOH, tolueneas depicted below:

Compounds of formula 1-j can undergo cyclization in the presence of Pdcatalyst with suitable ligands such as Pd(dppf)Cl₂CH₂Cl₂ or Pd(PPh₃)₂Cl₂to provide compounds of formula 1-k. The fluoro group in compounds offormula 1-k can be converted to a group of formula -L-R⁸ where L and R⁸are as described in the Summary by treating compound 1-k with a compoundof formula R⁸-LH where L is N, O, or S and R⁸ is a defined in theSummary by method well known in the art. Compounds of formula R⁸-LH arecommercially available or they can be prepared by methods well known inthe art. For example, 3-fluoro-5-hydroxybenzonitrile,3,5-difluorophenol, 3-chloro-5-fluorophenol,3-chloro-5-hydroxy-benzonitrile, 5-fluoropyridin-3-ol,5-chloropyridin-3-ol, 5-hydroxynicotinonitrile,3-fluoro-5-mercaptobenzonitrile, 3-amino-5-fluorobenzonitrile,3,3-difluorocyclobutan-1-ol, 3-amino-5-fluorobenzonitrile,3-fluoro-5-mercaptobenzonitrile, 3-chloro-5-mercaptobenzonitrile,3-amino-5-chlorobenzonitrile are commercially available.

Compounds of Formula (I) where R¹ is hydroxyl, R³, R⁴, R⁵, R⁶, R⁷, andR⁸ are as defined in the Summary (or any embodiments thereof), and R⁹and R² are combined to form oxo can be prepared as illustrated anddescribed in Scheme 2 below.

Compounds of Formula 1-k can be converted to compounds of Formula 1-1 bytreating it with an oxidative cleavage reagent such as NaIO₄ and RuCl₃hydrate under conditions well known in the art. The fluoro group incompounds of Formula 1-1 can be converted to a group of formula -L-R⁸where L and R⁸ are as described in the Summary by treating compound 1-1with a compound of formula R⁸-LH.

Compounds of Formula (I) can be converted to other compounds of Formula(I) by methods well known in the art. For example, compounds of Formula(I) where with R¹ is hydroxyl, R² is hydrogen and R⁹ is hydroxy orfluoro can be synthesized from the compounds of Formula (I) where R⁹ andR² are combined to form oxo by further functionalizing the carbonylgroup as illustrated and described in Methods (i) and (ii) below.

Method (i)

A compound of Formula (I) where R¹ is hydroxy, R⁹ and R² are combined toform oxo can be converted to a compound of Formula (I) where R¹ ishydroxy, R⁹ is hydroxy by treating it with reducing reagent such assodium borohydride under conditions well known in the art.

Method (ii)

A compound of Formula (I) where R¹ is hydroxy, R⁹ is hydroxy can beconverted to a compound of Formula (I) where R¹ is hydroxy, R⁹ is fluoroby treating it with fluorination reagent such as DAST under conditionswell known in the art.

Utility

The compounds disclosed herein are useful for the treatment of HIF-2αmediated diseases, which include but are not limited to, various typesof cancer, liver disease such as nonalcoholic steatohepatitis (NASH),inflammatory disease such as inflammatory bowel disease (IBD), pulmonarydiseases such as pulmonary arterial hypertension (PAH), and iron loaddisorders.

HIF-2α plays an important role in the initiation and progression of manyhuman cancers. Many extensive studies have demonstrated the criticalrole of increased HIF-2α activity in driving clear cell renal cellcarcinoma (ccRCC) (see review by Shen and Kaelin, Seminars in CancerBiology 23: 18-25, 2013). Abnormal HIF-2α activity is largely due toloss of function of a tumor suppressor, VHL. It is known that overeighty percent of ccRCC have defective VHL either through deletion,mutation or disturbed post-translational modification. Defective VHLleads to constitutively active HIF-α proteins regardless of oxygenlevel. Various studies employing gain-of-function and loss-of-functionapproaches in mouse models have demonstrated that HIF-2α is the keyoncogenic substrate of VHL (see Kondo, et al. Cancer Cell 1: 237-246,2002; Kondo, et al. PLoS Biology 1: 439-444, 2002; Maranchi, et al.Cancer Cell 1: 247-255, 2002; Zimmer, et al. Mol. Cancer Res 2: 89-95,2004). For example, knockdown of HIF-2α in VHL-null tumors inhibitedtumor formation; while reintroduction of VHL and overexpression ofHIF-2α overcame the tumor suppressive role of VHL. Moreover, singlenucleotide polymorphism in HIF-2α, is associated with resistant toPHD-mediated degradation, has been linked to an increased risk ofdeveloping RCC. In addition to serving as an archetypicaltumor-initiating event in ccRCC, the VHL-HIF-2α axis has also beenimplicated in ccRCC tumor metastasis through its downstream CXCR4 andCYTIP (see Vanharanta et al. Nature Medicine 19: 50-59, 2013; PeterStaller et al. Nature. 2003 Sep. 18; 425(6955):307-11). Taken together,these studies strongly support the potential therapeutic utility ofHIF-2α targeted agents for the treatment of ccRCC.

Defective VHL not only predisposes patients to kidney cancer (with a 70%lifetime risk), but also to hemangioblastomas, pheochromocytoma,enclolymphatic sac tumors and pancreatic neuroendocrine tumors. Tumorsderived from defective VHL are frequently driven by the constitutivelyactive downstream HIF-α proteins, with the majority of these dependenton HIF-2α activity (see Maher, et al. Eur. J. Hum. Genet. 19: 617-623,2011). Both genetic and epigenetic mechanisms can lead to the loss offunction in VHL. Epigenetic inactivation of VHL expression and thusconstitutive activation of HIF-α proteins has been found in many cancersincluding RCC, multiple myeloma, retinoblastoma, NSCLC, pancreaticendocrine tumors, squamous cell carcinoma, acute myeloid leukemia,myelodysplastic syndrome, and esophageal squamous cell carcinoma (seereviewed in Nguyen, et al. Arch. Phann. Res 36: 252-263, 2013). HIF-2αhas also been linked to cancers of the retina, adrenal gland andpancreas through both loss of function in VHL and activating mutationsin HIF-2α. Recently, gain-of-function HIF-2α mutations have beenidentified in erythrocytosis and paraganglioma with polycythemia (seeZhuang, et al. NEJM 367: 922-930, 2012; Percy, et al. NEJM 358: 162-168,2008; and Percy, et al. Am. J. Hematol. 87: 439-442, 2012). Notably,many of the known HIF-2α target gene products (e.g., VEGF, PDGF, andcyclin D1) have been demonstrated to play pivotal roles in cancersderived from kidney, liver, colon, lung, and brain. Thus, a HIF-2αtargeted therapy could be beneficial for the above cancers when drivenby these signaling events downstream of abnormal HIF-2α pathwayactivation. In addition to loss of function in VHL and activatingmutation of HIF-2α, HIF-α proteins are also frequently upregulated inthe intratumor environment of rapidly growing tumors, due to the hypoxiccondition resulting from poor vascularization in large tumors. Theactivated HIF-α pathways, in turn, further promotes tumor cell survivaland proliferation by transcriptionally upregulating various essentialfactors.

A large body of studies have demonstrated a correlation between HIF-2αoverexpression and poor prognosis in various cancers including cancersof astrocytoma, breast, cervical, colorectal, glioblastoma, glioma, headand neck, liver, non-small cell lung, melanoma, neuroblastoma, ovarian,and prostate, thereby supporting the pursuit of HIF-2α as a therapeutictarget in treating these cancers (see reviewed in Keith, et al. NatureRev. Cancer 12: 9-22, 2012). HIF-2α has been demonstrated to augment thegrowth of APC mutant colorectal cancer through its regulation of genesinvolved in proliferation, iron utilization and inflammation (see Xue,et al. Cancer Res 72: 2285-2293, 2012; and Xue and Shah, Carcinogenesis32: 163-169, 2013). In hepatocellular carcinoma (HCC), knock-down ofHIF-2α in preclinical models led to the inhibition of cell proliferationin vitro and tumor growth in vivo through the downregulation of VEGF andcyclin D 1 (see He, et al. Cancer Sci. 103: 528-534, 2012). In NSCLC,around 50% of patients exhibited overexpression of HIF-2α protein, whichstrongly correlates with higher VEGF expression and more importantly,reduced overall survival. Interestingly, HIF-1α does not correlate withreduced overall survival in lung cancer patients even though itsexpression is also often increased (see Giatromanolaki, et al. Br. J.Cancer 85: 881-890, 2001). Extensive studies in mice engineered withboth non-degradable HIF-2α and mutant KRAS tumors have demonstrated anincreased tumor burden and a decreased survival when compared to micewith only mutant KRAS expression (see Kim, et al. J. Clin. Invest. 119:2160-2170, 2009). These studies demonstrate that HIF-2α promotes tumorgrowth and progression in lung cancer, and also negatively correlateswith clinical prognosis.

HIF-2 as activity has been linked to the progression of chronicobstructive pulmonary disease (COPD), in addition to lung cancer, inmouse models (see Karoor, et al. Cancer Prev. Res. 5: 1061-1071, 2012).HIF-2α activity has also been demonstrated to be important in cancers ofthe central nervous system (see Holmquist-Mengelbier, et al. Cancer Cell10: 413-423, 2006 and Li, et al. Cancer Cell 15: 501-513, 2009). HIF-2αknockdown reduced tumor growth in preclinical animal models ofneuroblastoma, Conversely, increased level of HIF-2α correlated withadvanced disease, poor prognosis and higher VEGF levels, which likelycontribute to the poor clinical outcome. Similarly, higher HIF-2αexpression has been correlated with a poor survival in glioma.Experimentally, inhibition of HIF-2α in glioma stem cells reduced cellproliferation and survival in vitro and tumor initiation in vivo. WhileHIF-1α is expressed in both neural progenitors and brain tumor stemcells, HIF-2α is found exclusively in the latter. Moreover, survival ofglioma patients correlates to with HIF-2α, but not HIF-1α level.

One of downstream HIF-2α effector is cyclin D, an essential partner forthe activation of CDK4 and CDK6. Therefore, administration of a HIF-2αinhibitor with CDK4/6 inhibitors, including abemaciclib)(Verzenio®,palbociclib (Ibrance®) and ribociclib (Kisqali®) should result indownregulation of cyclin D, thereby increasing antiproliferative effectsof CDK4/6 inhibitors. A recent study (Nicholson et al Sci Signal. 2019Oct. 1; 12(601)) suggests that the antiproliferative effects of CDK4/6inhibition were synergistic with HIF-2α inhibition in HIF-2α-dependentVHL−/− ccRCC cells.

Radiation therapy is frequently used for approximately 50% of cancerpatients, either alone or in combination with other therapies. However,the hypoxia microenvironment within the tumor has long been associatedwith resistance to radiation therapy. Bhatt and co-workers found thatdecreased level of HIF-2α leads to increased sensitivity to ionizingradiation in renal cell carcinoma cell lines (see Bhatt, et al. BJU Int.102: 358-363, 2008). Furthermore, mechanistic studies from Bertout et.al, have demonstrated that HIF-2α inhibition enhances the effectivenessof radiation through increased p53-dependent apoptosis (see Bertout, etal. PNAS 106: 14391-14396, 2009). Thus, HIF-2α targeted therapy couldimprove the response to radiation therapy in various cancers.

Somatostatinomas are somatostatin-producing neuroendocrine tumors thatare rare but often malignant. It has been found that HIF-2α mutationslead to the disruption of the prolyl hydroxylation domain (PHD) ofHIF-2α, thus abolish the modification by PHDs, and subsequently reduceHIF-2α degradation mediated by VHL (see Yang, et al. Blood. 121:2563-2566, 2013). The stabilized HIF-2α can then translocate to thenucleus, driving increased expression of hypoxia-related genes tocontribute to somatostatinoma. Thus, a HIF-2α inhibitor will provide analternative approach in treating somatostatinoma.

Polycythaemia is a hematologic disorder characterized by elevatedhematocrit (the volume percentage of red blood cells in the blood), alsoknown as erythrocytosis. Gain-of-function mutations in HIF-2α areassociated with autosomal dominant erythrocytosis (see Percy, et al. N.Engl. J. Med. 358: 162-8, 2008 and Wilson et al. Case Rep Hematol.6373706, 2016). In addition, mutations in PHD of HIF-2α, which isresponsible in signaling HIF-2α for ubiquitination and degradation byVHL, have also been found to drive polycythaemia. Thus, inhibitingHIF-2α n, which is stabilized either by gain of function HIF-2αmutations or by loss of function mutations in PHD, VHL, by an HIF-2αinhibitor should be able to suppress HIF-2α downstream genes, such asEPO and thereby reducing hematocrit of polycythaemia.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrinetumors that often develop on a background of predisposing geneticmutations, including loss of function in VHL or PHD2 or activatingmutations of HIF-2α, all of which result in highly expressed HIF-2αprotein and subsequently downstream genes to promote oncogenicprogression (see Dahia, Nat Rev Cancer. 14:108-19, 2014). Furthermore,germline heterozygous mutations in genes encoding succinatedehydrogenase (SDH) subunits and the SDH complex assembly factor 2protein (SDHAF2) have been described in patients with hereditaryphaeochromocytoma and paraganglioma (PPGL). These mutations can lead tothe accumulation of succinate, which in turn causes an inhibition ofprolyl-hydroxylases that is essential in mediatingubiquitination/degradation of HIF proteins by VHL complex. Pituitaryadenoma has been frequently found to be co-existing with PPGLs. Thus,inhibiting HIF-2α should be useful for treating both PPGLs and pituitarytumors. Succinate dehydrogenase subunits mutations have also beenassociated with gastrointestinal stromal tumors (GIST), thus supportingexploration of HIF-2α inhibitor for the treatment of GIST (see Janeway,et al. Proc. Natl Acad. Sci. USA 108: 314-318, 2011).

Loss-of-function mutations of fumarate hydratase (FH) predisposepatients to the autosomal dominant syndrome of both cutaneous anduterine leiomyomatosis. It has been suggested that activation of HIFproteins contributes to FH-associated tumor development by activation ofhypoxia pathways. (see O'Flaherty, et al. Hum Mol Genet. 19: 3844-3851,2010 and Wei, et al. J Med Genet. 43:18-27, 2006). Furthermore, highexpression of HIF-2α is found in leiomyosarcomas, a rare neoplasm ofsmooth-muscle origin (see Mayer, et al. Cancer Res. 68: 4719, 2008)Thus, inhibition of HIF-2α could be beneficial in treating bothleiomyomas and leiomyosarcomas.

Retinal capillary hemangioblastomas can be the ocular manifestations ofVHL diseases, which are caused by loss of tumor suppressor VHL.Upregulation of HIF-2α upon loss of VHL has been detected in retinalhemangioblastoma patients and is indicated to contribute to theaggressive course of retinal hemangioblastomas, resulting in theresistance to multiple anti-VEGF and radiation therapies (see Wang, etal. Graefes Arch. Clin. Exp. Ophthalmol. 252:1319-1327, 2014). Moreover,uncontrolled blood vessel growth is a central pathological component ofmany human blindness disorders, including diabetic retinopathy,age-related macular degeneration, glaucoma, and retinopathy ofprematurity. Neuronal cell death and vision loss observed in thesediseases are often caused by aberrant, leaky vessels, results ofpathological neovascularization (see Krock, et al. Genes Cancer. 2:1117-1133, 2011). Given the causal role of HIFs in neovascularization,inhibitor of HIF-2α may have potential utility in treating variousdiseases of blindness. In fact, systemic reduction of HIF-2α expressionwith a hypomorphic Hif-2α allele caused marked decreases in retinalneovascularization that was accompanied by defects in EPO expression(see Morita, et al. EMBO J. 22: 1134-46, 2003).

In addition to a direct role in promoting the initiation, progressionand metastasis of tumor cells (e.g. ccRCC), HIF-2α also indirectlycontributes to tumorigenesis through augmenting the immunosuppressiveeffect of hypoxia within the tumor microenvironment. Expression ofHIF-2α has been detected in cells of the myeloid lineage (see Talks K L,et dal. Am J Pathol. 2000; 157(2):411-421). For example, HIF-2α is shownto favor the polarization of macrophages to the immunosuppressive M2phenotype and enhances migration and invasion of tumor-associatedmacrophages (see Imtiyaz H Z et al. J Clin Invest. 2010;120(8):2699-2714). Thus, increased level of HIF-2α in tumor-associatedmacrophages (TAMs) is associated with high-grade human tumors andcorrelates with poor prognosis. Furthermore, HIF-2α can indirectlypromote additional immunosuppressive pathways (e.g. adenosine andarginase etc.) by modulating the expression of key signaling regulatorssuch as adenosine A2B/A2A receptors and arginase. These data supportthat HIF-2α is a potential therapeutic target for treating a broaderrange of inflammatory disorders and cancer either as a single agent orin combination with other therapeutic agents e.g., immunotherapies.

Due to the key roles of HIF-2α proteins in regulating physiologicalresponse to the fluctuation of oxygen levels, they have been causallyassociated with many hypoxia-related pathological processes in additionto cancer. One such disease is PAH, a debilitating and life-threateningdisease with very poor prognosis. Recent studies demonstrated thatHIF-2α contributes to the process of hypoxic pulmonary vascularremodeling, reduced plasticity of the vascular bed, and ultimately,debilitating PAH (see Andrew S., et al. Proc Natl Acad Sci USA. 2016Aug. 2; 113(31): 8801-8806, Tang H, et al. Am J Physiol Lung Cell MolPhysiol. 2018 Feb. 1; 314(2):L256-L275.). These studies offered newunderstanding in the role of pulmonary endothelial HIF-2α in regulatingthe pulmonary vascular response to hypoxia, and offer an much needed newtherapeutic strategy by targeting HIF-2α. Another example ofhypoxia-related pathological processes is IBD, a chronic relapsinginflammatory disease of the intestine. It is found that intestinalinflammation and subsequently IBD arose when a dysregulated epithelialoxygen tension occurs and intensifies across epithelial villi in theintestine (see Shah Y. M., Molecular and Cellular Pediatrics, 2016December; 3(1):1). HIF-2α activation contributes to IBD, while HIF-1α inintestinal epithelial cells is considered as a major protective factorin IBD (see Karhausen J, et al. J Clin Invest. 2004; 114(8):1098-1106;Furuta G T, et al. J Exp Med. 2001; 193(9):1027-1034). Mechanistically,HIF-2α activation not only leads to the upregulation of pro-inflammatorycytokines which promotes IBD directly, but also results in loss ofintestine barrier integrity, thus indirectly contributes to themanifestation of IBD. (see Xue X, et al. Gastroenterology. 2013;145(4):831-841; Glover L E, et al. Proc Natl Acad Sci USA. 2013;110(49):19820-19825). Therefore, an HIF-2α inhibitor holds the promiseof reverting the pro-inflammatory condition and increasing theintestinal barrier integrity, thus alleviate the symptoms of IBD.

HIF-2α inhibitor also represents a novel therapeutic approach in NASH,for which limited therapeutic options are available. A recent studyshowed that an intestine-specific disruption of HIF-2α led to asignificant reduction of hepatic steatosis and obesity induced byhigh-fat-diet. Mechanistically, intestine HIF-2α positively regulatesthe gene encoding neuraminidase 3, thus regulates ceramide metabolismwhich contributes to the development of NASH (see Xie C, et al. Nat Med.2017 November; 23(11):1298-1308.). Therefore, an HIF-2α inhibitor shouldhave preventive and therapeutic effects on metabolic disorders, such asNASH.

Several connections between the level of HIF-2α and iron homeostasishave been identified (see Peyssonnaux C et al, Cell Cycle. 2008;7(1):28-32). Multiple studies have demonstrated the important role ofHIF-2α in iron load disorders. HIF-2α, not HIF-1α, has emerged as animportant “local” regulator of intestinal iron status through itsregulation of various genes essential in iron transport and absorption(see Mastrogiannaki M, et al. J Clin Invest. 2009; 119(5):1159-1166).Therefore, a small molecule inhibitor that targets HIF-2α holds promiseof improving iron homeostasis in patients with iron disorders.

Accordingly, the present invention provides a method for treating orlessening the severity of a disease, condition, or disorder whereactivation or over activation of HIF-2α is implicated in the diseasestate. In another aspect, the present disclosure provides a method oftreating renal cell carcinoma of a subject with a compound disclosedherein or a pharmaceutically acceptable salt thereof.

HIF-2α inhibitors also have therapeutic potentials for a broad range ofnon-cancer indications including but not limited to NASH, IBD, PAH, andiron overload.

Testing

The HIF2α inhibitory activity of the compounds of the present disclosurecan be tested using the in vitro assay described in Biological Examples1 below.

Pharmaceutical Compositions

In general, the compounds of this disclosure will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Therapeuticallyeffective amounts of compounds this disclosure may range from about 0.01to about 500 mg per kg patient body weight per day, which can beadministered in single or multiple doses. A suitable dosage level may befrom about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kgper day. A suitable dosage level may be about 0.01 to about 250 mg/kgper day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50mg/kg per day. Within this range the dosage can be about 0.05 to about0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oraladministration, the compositions can be provided in the form of tabletscontaining about 1.0 to about 1000 milligrams of the active ingredient,particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250,300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the activeingredient. The actual amount of the compound of this disclosure, i.e.,the active ingredient, will depend upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe patient, the potency of the compound being utilized, the route andform of administration, and other factors.

In general, compounds of this disclosure will be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is oral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Compositions can take the form of tablets, pills,capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules, including enteric coated or delayedrelease tablets, pills or capsules are preferred) and thebioavailability of the drug substance.

The compositions are comprised of in general, a compound of thisdisclosure in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the compound of thisdisclosure. Such excipient may be any solid, liquid, semi-solid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds disclosed herein may be administered topically, thatis by non-systemic administration. This includes the application of acompound disclosed herein externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose. The active ingredient for topical administration maycomprise, for example, from 0.001% to 10% w/w (by weight) of theformulation. In certain embodiments, the active ingredient may compriseas much as 10% w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/wof the formulation.

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray. Pressurized packs maycomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, thecompounds according to the disclosure may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form, in for example, capsules, cartridges,gelatin or blister packs from which the powder may be administered withthe aid of an inhalator or insufflator. Other suitable pharmaceuticalexcipients and their formulations are described in Remington'sPharmaceutical Sciences, edited by E. W. Martin (Mack PublishingCompany, 20th ed., 2000).

The level of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt. %) basis, from about 0.01-99.99wt. % of a compound of this disclosure based on the total formulation,with the balance being one or more suitable pharmaceutical excipients.For example, the compound is present at a level of about 1-80 wt. %.

Combinations and Combination Therapies

The compounds of this disclosure may be used in combination with one ormore other drugs in the treatment of diseases or conditions for whichcompounds of this disclosure or the other drugs may have utility. Suchother drug(s) may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound of thepresent disclosure. When a compound of this disclosure is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of the present disclosure is preferred. However, thecombination therapy may also include therapies in which the compound ofthis disclosure and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundsof the present disclosure and the other active ingredients may be usedin lower doses than when each is used singly.

Accordingly, the pharmaceutical compositions of the present disclosurealso include those that contain one or more other drugs, in addition toa compound of the present disclosure.

The above combinations include combinations of a compound of thisdisclosure not only with one other drug, but also with two or more otheractive drugs. Likewise, a compound of this disclosure may be used incombination with other drugs that are used in the prevention, treatment,control, amelioration, or reduction of risk of the diseases orconditions for which a compound of this disclosure is useful. Such otherdrugs may be administered, by a route and in an amount commonly usedtherefore, contemporaneously or sequentially with a compound of thepresent disclosure. When a compound of this disclosure is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthis disclosure can be used. Accordingly, the pharmaceuticalcompositions of the present disclosure also include those that alsocontain one or more other active ingredients, in addition to a compoundof this disclosure. The weight ratio of the compound of this disclosureto the second active ingredient may be varied and will depend upon theeffective dose of each ingredient. Generally, an effective dose of eachwill be used.

Where the subject in need is suffering from or at risk of suffering fromcancer, the subject can be treated with a compound of this disclosure inany combination with one or more other anti-cancer agents. In someembodiments, one or more of the anti-cancer agents are proapoptoticagents. Examples of anti-cancer agents include, but are not limited to,any of the following: gossyphol, genasense, polyphenol E, Chlorofusin,all trans-retinoic acid (ATRA), bryostatin, tumor necrosisfactor-related apoptosis-inducing ligand (TRAIL),5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin,vincristine, etoposide, gemcitabine, imatinib (Gleevec™) geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352,Taxol™, also referred to as “paclitaxel”, which is a well-knownanti-cancer drug which acts by enhancing and stabilizing microtubuleformation, and analogs of Taxol™., such as Taxotere™. Compounds thathave the basic taxane skeleton as a common structure feature, have alsobeen shown to have the ability to arrest cells in the G2-M phases due tostabilized microtubules and may be useful for treating cancer incombination with the compounds described herein.

Suitable anti-cancer agents also include inhibitors of kinasesassociated cell proliferative disorder. These kinases include but notlimited to Aurora-A, BTK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK5, CDK7,CDK8, CDK9, ephrin receptor kinases, CHK1, CHK2, SRC, Yes, Fyn, Lck,Fer, Fes, Syk, Itk, Bmx, GSK3, JNK, MEK, PAK1, PAK2, PAK3, PAK4, PDK1,PKA, PKC, RAF, Rsk and SGK. In particular, inhibitors of CDK4/6,including abemaciclib (Verzenio), palbociclib (Ibrance) and ribociclib(Kisqali), have the potential to be synergistic with HIF-2α inhibitorsand reverse the resistance to HIF-2α inhibition; mitogen-activatedprotein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901,ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002;Syk inhibitors; antibodies (e.g., rituxan); MET inhibitor such asforetinib, carbozantinib, or crizotinib; VEGFR inhibitor such assunitinib, sorafenib, regorafinib, lenvatinib, vandetanib,carbozantinib, axitinib; EGFR inhibitor such as afatinib, brivanib,carbozatinib, erlotinib, gefitinib, neratinib, lapatinib; PI3K inhibitorsuch as XL147, XL765, BKM120 (buparlisib), GDC-0941, BYL719, IPI145,BAY80-6946. BEX235 (dactolisib), CAL101 (idelalisib), GSK2636771,TG100-115; MTOR inhibitor such as rapamycin (sirolimus), temsirolimus,everolimus, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, GDC0349;MEK inhibitor such as AZD6244, trametinib, PD184352, pimasertinib,GDC-0973, AZD8330; CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1Rantibodies (IMC-054, RG7155, etc); TGF beta receptor kinase inhibitorsuch as LY2157299; BTK inhibitor such as ibrutinib.

Other anti-cancer agents include proteasome inhibitor such ascarfilzomib, MLN9708, delanzomib, or bortezomib; BET inhibitors such asINCB054329, OTX015, CPI-0610; LSD1 inhibitors such as GSK2979552,INCB059872; HDAC inhibitors such as panobinostat, vorinostat; DNA methyltransferase inhibitors such as azacytidine, decitabine), and otherepigenetic modulator; SHP-2 inhibitor such as TNO155; Bcl2 inhibitorABT-199, and other Bcl-2 family protein inhibitors; HIF-2α inhibitorssuch as PT2977 and PT2385; Beta catenin pathway inhibitors, notchpathway inhibitors and hedgehog pathway inhibitors; Antibodies or othertherapeutic proteins against VEGF include bevacizumab and aflibercept.

Other anti-cancer agents/drugs that can be used in combination with thecompounds of the invention include, but are not limited to, liver Xreceptor (LXR) modulators, including LXR agonists and LXR beta-selectiveagonists; aryl hydrocarbon receptor (AhR) inhibitors;

Other anti-cancer agents that can be employed in combination with acompound of this disclosure include Adriamycin, Dactinomycin, Bleomycin,Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride;acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine;gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride;ifosfamide; ilmofosine; interleukin II (including recombinantinterleukin II, or Ri12), interferon alfa-2a; interferon alfa-2b;interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferongamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate;letrozole; leuprolide acetate; liarozole hydrochloride; lometrexolsodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine;mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantronehydrochloride; temoporfin; teniposide; teroxirone; testolactone;thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifenecitrate; trestolone acetate; triciribine phosphate; trimetrexate;trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;zinostatin; zorubicin hydrochloride.

Other anti-cancer agents that can be employed in combination with acompound of the disclosure include: 20-epi-1, 25 dihydroxyvitamin D3;5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;antagonist D; antagonist G; antarelix; anti-dorsalizing morphogeneticprotein-1; antiandrogen, prostatic carcinoma; antiestrogen;antineoplaston; antisense oligonucleotides; aphidicolin glycinate;apoptosis gene modulators; apoptosis regulators; apurinic acid;ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; Bfgfinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; mopidamol; multiple drugresistance gene inhibitor; multiple tumor suppressor 1-based therapy;mustard anticancer agent; mycaperoxide B; mycobacterial cell wallextract; myriaporone; N-acetyldinaline; N-substituted benzamides;nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin;nartograstim; nedaplatin; nemorubicin; neridronic acid; neutralendopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxideantioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone;oligonucleotides; onapristone; ondansetron; oracin; oral cytokineinducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine;palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin;pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium;pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol;phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetinB; plasminogen activator inhibitor; platinum complex; platinumcompounds; platinum-triamine complex; porfimer sodium; porfiromycin;prednisone; propyl bis-acridone; prostaglandin J2; proteasomeinhibitors; protein A-based immune modulator; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; R.sub.11 retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived 1; sense oligonucleotides; signaltransduction inhibitors; signal transduction modulators; single chainantigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stem cell inhibitor; stem-cell division inhibitors;stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactiveintestinal peptide antagonist; suradista; suramin; swainsonine;synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide;tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium;telomerase inhibitors; temoporfin; temozolomide; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; totipotent stem cell factor; translation inhibitors;tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin;tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBCinhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor;urokinase receptor antagonists; vapreotide; variolin B; vector system,erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin;vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin;zilascorb; and zinostatin stimalamer.

Yet other anticancer agents that can be employed in combination with acompound of this disclosure include alkylating agents, antimetabolites,natural products, or hormones, e.g., nitrogen mustards (e.g.,mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin).

Examples of natural products useful in combination with a compound ofthis disclosure include but are not limited to vinca alkaloids (e.g.,vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g.,daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase),or biological response modifiers (e.g., interferon alpha).

Examples of alkylating agents that can be employed in combination with acompound of this disclosure) include, but are not limited to, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,melphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude, but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

Examples of hormones and antagonists useful in combination a compound ofthis disclosure include, but are not limited to, adrenocorticosteroids(e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate,megestrol acetate, medroxyprogesterone acetate), estrogens (e.g.,diethylstilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen),androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen(e.g., flutamide), gonadotropin releasing hormone analog (e.g.,leuprolide). Other agents that can be used in the methods andcompositions described herein for the treatment or prevention of cancerinclude platinum coordination complexes (e.g., cisplatin, carboblatin),anthracenedione (e.g., mitoxantrone), substituted urea (e.g.,hydroxyurea), methyl hydrazine derivative (e.g., procarbazine),adrenocortical suppressant (e.g., mitotane, aminoglutethimide).

Other anti-cancer agents that can be employed in combination with acompound of the disclosure include: anti-cancer agents which act byarresting cells in the G2-M phases due to stabilized microtubules andinclude Erbulozole (also known as R-55104), Dolastatin 10 (also known asDLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980),Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296),ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such asAltorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1,Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5,Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9),Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356),Epothilones (such as Epothilone A, Epothilone B, Epothilone C (alsoknown as desoxyepothilone A or dEpoA), Epothilone D (also referred to asKOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F,Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D(also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone),Auristatin PE (also known as NSC-654663), Soblidotin (also known asTZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578(Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559(Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358(Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164(Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences),BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960(Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/KyowaHakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, alsoknown as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known asAVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide,Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969),T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1(Parker Hughes Institute, also known as DDE-261 and WHI-261), H10(Kansas State University), H16 (Kansas State University), Oncocidin A1(also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute),Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1(Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine(also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphatesodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411(Sanofi).

One or more additional immune checkpoint inhibitors can be used incombination with a compound as described herein for treatment ofHIF-2α-associated diseases, disorders or conditions. Exemplary immunecheckpoint inhibitors include inhibitors (smack molecules or biologics)against immune checkpoint molecules such as CD27, CD28, CD40, CD122,CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma,TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, SHP-2,B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1and PD-L2. In some embodiments, the immune checkpoint molecule is astimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,OX40, GITR, CD137 and STING. In some embodiments, the immune checkpointmolecule is an inhibitory checkpoint molecule selected from B7-H3,B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3, CD96,TIGIT and VISTA. In some embodiments, the compounds provided herein canbe used in combination with one or more agents selected from KIRinhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4inhibitors and TGFR beta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab, or pembrolizumab or PDR001. In some embodiments, the anti-PD1antibody is pembrolizumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) orMEDI4736 (durvalumab).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. Insome embodiments, the inhibitor of an immune checkpoint molecule is aninhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, theanti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, theinhibitor of an immune checkpoint molecule is an inhibitor of GITR,e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibodyis TRX518 or, MK-4166, INCAGN01876 or MK-1248. In some embodiments, theinhibitor of an immune checkpoint molecule is an inhibitor of OX40,e.g., an anti-OX40 antibody or OX40L fusion protein. In someembodiments, the anti-OX40 antibody is MEDI0562 or, INCAGN01949,GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In someembodiments, the OX40L fusion protein is MEDI6383.

Compounds of the invention can also be used to increase or enhance animmune response, including increasing the immune response to an antigen;to improve immunization, including increasing vaccine efficacy; and toincrease inflammation. In some embodiments, the compounds of theinvention can be sued to enhance the immune response to vaccinesincluding, but not limited, Listeria vaccines, oncolytic viral vaccines,and cancer vaccines such as GVAX® (granulocyte-macrophagecolony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine).Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses. Other immune-modulatory agents alsoinclude those that block immune cell migration such as antagonists tochemokine receptors, including CCR2 and CCR4; Sting agonists and Tollreceptor agonists.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer. Compounds of thisapplication may be effective in combination with CAR (Chimeric antigenreceptor) T cell treatment as a booster for T cell activation

EXAMPLES

The following preparations of compounds of Formula (IA)/(I) are given toenable those skilled in the art to more clearly understand and topractice the present disclosure. They should not be considered aslimiting the scope of the disclosure, but merely as being illustrativeand representative thereof.

Example 1 Synthesis of3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

Step 1: ethyl3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate

To a stirred mixture of zinc (6.97 g, 106.56 mmol, 1.03 equiv.),1,2-dibromoethane (388.71 mg, 2.069 mmol, 0.02 equiv.) andchlorotrimethylsilane (1.12 g, 10.31 mmol, 0.10 equiv.) in THF (200 mL)was added a solution of ethyl 2-bromo-2,2-difluoroacetate (21.0 g,103.45 mmol, 1.0 equiv.) and 2-bromo-4-fluorobenzaldehyde (21.0 g,103.45 mmol, 1.0 equiv.) in THF (100 mL) dropwise at room temperatureunder nitrogen atmosphere. The resulting mixture was stirred for 16 h at75° C. under nitrogen atmosphere. The reaction was cooled and quenchedwith ice/water. The organic solvent was removed under vacuum and theresulting mixture was extracted with EtOAc. The combined organic layerwas washed with water, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (5:1), to afford the title compound(18 g, 53.2%) as a yellow oil.

Step 2: ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-oxopropanoate

To a stirred solution of ethyl3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate (16 g, 48.9mmol, 1.0 equiv.) in CH₃CN (200 mL) was added 2-iodoxybenzoic acid (27.4g, 97.83 mmol, 2.0 equiv.) at room temperature and the resulting mixturewas stirred for 3 h at 80° C. The reaction solution was then cooled toroom temperature, filtered and the filter cake was washed with EtOAc.The filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE/EtOAc(10:1), to afford the title compound (10.3 g, 64.8%) as a yellow oil.

Step 3: ethyl 3-(2-bromo-4-fluorophenyl)-2,2,3,3-tetrafluoropropanoate

To a stirred solution of ethyl3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-oxopropanoate (6.1 g, 18.8mmol, 1.0 equiv.) in CHCl₃ (6 mL) was added DAST (30.25 g, 187.6 mmol,10.0 equiv.) dropwise at room temperature and the resulting mixture wasstirred for 16 h at 70° C. under nitrogen atmosphere. The reactionsolution was allowed to cool to room temperature and quenched withice/water. The mixture was extracted with DCM. The organic layer wasdried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby silica gel column chromatography, eluted with PE/EtOAc (10:1), toafford the title compound (2.4 g, 36.8%) as yellow oil.

Step 4: 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one

To a stirred solution of ethyl3-(2-bromo-4-fluorophenyl)-2,2,3,3-tetrafluoropropanoate (4.20 g, 12.10mmol, 1.0 equiv.) in THF (50 mL) was added n-BuLi (2.5 M, 7.26 mL, 18.15mmol, 1.5 equiv.) dropwise at −78° C. under nitrogen atmosphere and theresulting mixture was stirred for 2 h between −70° C. and −80° C. undernitrogen atmosphere. The reaction was quenched with saturated NH₄Cl(aq.) and extracted with EtOAc. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography, eluted with PE/EtOAc(20:1), to afford the title compound (2.25 g, 83.7%).

Step 5: 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol

To a stirred solution of2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (300 mg, 1.35 mmol, 1.0equiv.) and triethylamine (273.35 mg, 2.70 mmol, 2.0 equiv.) in DCM (3mL) was added formic acid (186.49 mg, 4.05 mmol, 3.0 equiv.) dropwise at0° C., followed by the addition of RuCl(P-cymene)[(S,S)-Ts-DPEN] (8.59mg, 0.014 mmol, 0.01 equiv). The resulting mixture was stirred for 3 hat room temperature under nitrogen atmosphere then washed with water.The organic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (5:1), to afford the title compound(300 mg, 99.1%).

Step 6: 7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol

To a stirred solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol(2500 mg, 11.154 mmol, 1.00 equiv.) in tetrahydrofuran (60 mL) was addedLDA (2.0 M, 16.73 mL, 33.463 mmol, 3.00 equiv.) dropwise at −78° C.under nitrogen atmosphere. The resulting mixture was warmed to −30° C.over 30 min and stirred for additional 30 min at −30° C. To the abovemixture was added a solution of carbon tetrabromide (3699.05 mg, 11.154mmol, 1.00 equiv.) in THF dropwise at −78° C. The resulting mixture wasallowed warm to −30° C. over 30 min and stirred for additional 30 min at−30° C. The reaction was quenched with saturated NH₄Cl (aq.) at −30° C.The resulting mixture was extracted with EtOAc and the organic layer waswashed with brine, dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE/EtOAc(10:1), to afford the title compound (2600 mg, 76.9%) as a light yellowoil. MS (ES, m/z): [M−H]⁻=300.9, 302.9.

Step 7: 7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one

To a stirred mixture of7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol (2.63 g, 8.679mmol, 1.00 equiv.) in CH₃CN (45 mL) was added IBX (4.86 g, 17.356 mmol,2.00 equiv) at room temperature. The resulting mixture was stirred for 3h at 80° C., then cooled and filtered. The filter cake was washed withEtOAc. The combined filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith PE/EtOAc (10:1), to afford the title compound (1.8 g, 68.9%) as anoff-white solid.

Step 8: 1-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol

To a stirred solution of7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (100 mg, 0.332mmol, 1.00 equiv.) in THF (3 mL) was added allylmagnesium bromide (1.0M, 0.50 mL, 0.50 mmol, 1.50 equiv.) dropwise at −78° C. under nitrogenatmosphere. The resulting mixture was stirred for 1 h at −78° C. undernitrogen atmosphere. The reaction was quenched with saturated NH₄Cl(aq.). The resulting mixture was extracted with EtOAc and the organiclayer was dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with PE/EtOAc (5:1), to affordthe title compound (90 mg, 79.0%) as a yellow oil. MS (ES, m/z):[M−H]⁻=340.9, 342.9.

Step 9:3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol

To a stirred mixture of1-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol (1050mg, 3.060 mmol, 1.00 equiv.) in DMF (25 mL) were added AcONa (753.17 mg,9.181 mmol, 3.00 equiv.) and Pd(dppf)Cl₂·CH₂Cl₂ (249.93 mg, 0.306 mmol,0.10 equiv.) at room temperature. The resulting mixture was stirred for3 h at 100° C. under nitrogen atmosphere. The resulting mixture wasdiluted with water and extracted with EtOAc. The combined organic layerswere washed with water and brine, dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withPE/EtOAc (5:1), to afford the title compound (370 mg, 46.1%) as a lightyellow oil.

Step 10:3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

To a stirred mixture of3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol(40 mg, 0.15 mmol, 1.00 equiv.) and 3-fluoro-5-hydroxybenzonitrile(20.92 mg, 0.153 mmol, 1.00 equiv.) in DMF (1 mL) was added Cs₂CO₃(49.71 mg, 0.15 mmol, 1.00 equiv.) at room temperature. The resultingmixture was stirred for 24 h at 100° C. The resulting mixture wasfiltered and the filtrate was purified by Prep-HPLC to afford (16.77 mg,29.0%). MS (ES, m/z): [M−H]⁻=378.1.

Example 2 Synthesis of3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

Step 1:3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one

To a stirred mixture of3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol(320 mg, 1.22 mmol, 1.00 equiv.) in a mixed solvent (DCM/CH₃CN/H₂O=3mL/3 mL/4.50 mL) were added NaIO₄ (1044.25 mg, 4.882 mmol, 4.00 equiv.)and RuCl₃.H₂O (13.76 mg, 0.061 mmol, 0.05 equiv.) at room temperature.The resulting mixture was stirred for 6 h at room temperature. Theresulting mixture was diluted with water and extracted with DCM. Thecombined organic layers were washed with water and brine, dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (3:1), to afford the title compound(250 mg, 77.5%) as a white solid. MS (ES, m/z): [M−H]⁻=263.0.

Step 2:3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

To a stirred mixture of3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one(200 mg, 0.757 mmol, 1.00 equiv.) and 3-fluoro-5-hydroxybenzonitrile(103.81 mg, 0.757 mmol, 1.0 equiv.) in DMF (3 mL) was added Cs₂CO₃(246.69 mg, 0.76 mmol, 1.0 equiv.) at room temperature. The resultingmixture was stirred for 16 h at room temperature. The resulting mixturewas diluted with water and extracted with EtOAc. The combined organiclayers were washed with water and brine, dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith PE/EtOAc (3:1), to afford the title compound (200 mg, 69.3%) as awhite semi-solid. MS (ES, m/z): [M−H]⁻=380.0.

Example 3 Synthesis of3-fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

To a solution of3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile(40 mg, 0.105 mmol, 1.00 equiv.) in MeOH (1 mL) was added NaBH₄ (7.94mg, 0.210 mmol, 2.0 equiv.) at room temperature. The resulting mixturewas stirred for 3 h at room temperature. The reaction was quenched withaq. HCl (2.0 M) at room temperature to pH=7. The resulting mixture wasconcentrated under vacuum. The residue was diluted with water andextracted with EtOAc. The combined organic layers were washed withwater, dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified byprep-TLC, eluted with PE/EtOAc (3:1), to afford the title compound (40mg, 99.5%) as a colorless oil. MS (ES, m/z): [M−H]⁻=382.0.

Example 4 Synthesis of3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile[4]

To a stirred solution of3-fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile(20 mg, 0.05 mmol, 1.00 equiv.) in DCM (0.5 mL) was added DAST (6.73 mg,0.04 mmol, 0.80 equiv.) dropwise at −50° C. The resulting mixture wasstirred for 30 min at −50° C.-−40° C. The reaction mixture was quenchedwith NaHCO₃ (aq.) and extracted with DCM. The organic layer was driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by Prep-HPLC to affordthe title compound (4.3 mg, 21.3%) as a white solid. MS (ES, m/z):[M−H]⁻=384.1.

Example 5 Synthesis of1,3,3,4,4-pentafluoro-7-((5-fluoropyridin-3-yl)oxy)-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol

Step 1:3,3,4,4-tetrafluoro-7-((5-fluoropyridin-3-yl)oxy)-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one

To a stirred mixture of3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one (95 mg, 0.36 mmol, 1.00 equiv.) and 5-fluoropyridin-3-ol (41mg, 0.36 mmol, 1.00 equiv.) in DMF (2.00 mL) was added Cs₂CO₃ (128.90mg, 0.40 mmol, 1.10 equiv.) at room temperature under nitrogenatmosphere. After stirring for 4 h at room temperature, the reactionmixture was quenched with water at 0° C. The resulting mixture wasextracted with EtOAc. The combined organic layers were washed with brineand dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified byPrep-TLC (PE/EtOAc=3/1) to afford the title compound (85 mg, 66%) as awhite solid. MS (ES, m/z): [M+1]⁺=358.1.

Step 2:3,3,4,4-tetrafluoro-7-((5-fluoropyridin-3-yl)oxy)-1,2,3,4-tetrahydro-2aH-cyclopenta-[cd]indene-1,2a-diol

To a stirred solution of3,3,4,4-tetrafluoro-7-((5-fluoropyridin-3-yl)oxy)-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one(85 mg, 0.24 mmol, 1.00 equiv.) in MeOH (1.50 mL) was added NaBH₄ (18mg, 0.48 mmol, 2.00 equiv.) at room temperature. After stirring for 1 hat room temperature, the reaction mixture was quenched with saturatedNH₄Cl (aq.) at 0° C. The resulting mixture was extracted with EtOAc andthe combined organic layers were washed with brine and dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with EtOAc/PE (0-60%), to afford the titlecompound (80 mg, 93.7%) as a light yellow solid. MS (ES, m/z):[M+1]⁺=360.1.

Step 3:1,3,3,4,4-pentafluoro-7-((5-fluoropyridin-3-yl)oxy)-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol

To a stirred solution of3,3,4,4-tetrafluoro-7-((5-fluoropyridin-3-yl)oxy)-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]indene-1,2a-diol(30 mg, 0.08 mmol, 1.00 equiv.) in THF (1.00 mL) was added DAST (20 mg,0.12 mmol, 1.50 equiv.) at −50° C. under nitrogen atmosphere. Afterstirring for 2 h at −50-−30° C., the reaction mixture was quenched withsaturated NaHCO₃ (aq.) at 0° C. The resulting mixture was extracted withEtOAc and the combined organic layers were washed with brine and driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure. The crude product was purified by Prep-HPLC toafford the title compound (3 mg, 10%) as a white solid. MS (ES, m/z):[M+1]⁺=362.1.

Example 6 Synthesis of3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydrospiro-[cyclopenta[cd]indene-1,1′-cyclopropan]-7-yl)oxy)benzonitrile

To a stirred mixture of diethylzinc (0.53 mL, 0.53 mmol, 1.0 M inhexane) in DCM (3 mL) was added TFA (60 mg, 0.526 mmol, 4.00 equiv.)dropwise at 0° C. under nitrogen atmosphere. The resulting mixture wasstirred for 10 min at 0° C. To the above mixture was added CH₂I₂ (141mg, 0.53 mmol, 4.0 equiv.) dropwise at 0° C. The resulting mixture wasstirred for additional 10 min at 0° C., followed by the addition of3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile(50 mg, 0.132 mmol, 1.00 equiv.). The reaction mixture was stirred for10 min at 0° C., then stirred for additional 1 h at room temperature.The reaction mixture was quenched with water and extracted with CH₂Cl₂.The combined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure and thecrude product was purified by Prep-HPLC to afford the title compound(5.6 mg, 10.8%) as a white solid. MS (ES, m/z): [M−H]⁻=392.1.

Example 7 Synthesis of3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

To a stirred mixture of3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile(30 mg, 0.08 mmol, 1.00 equiv.) and phenyl sulfide (1.47 mg, 0.008 mmol,0.10 equiv.) in ethyl acetate (3 mL) and CH₃OH (3 mL) was added 10% Pd/C(20 mg) at room temperature. The resulting mixture was stirred for 48 hat room temperature under hydrogen atmosphere then filtered. Thefiltrate was concentrated under reduced pressure and the crude productwas purified by Prep-HPLC to afford the title compound (9 mg, 30%) as awhite solid. MS (ES, m/z): [M−H]⁻=380.1.

Example 8 Synthesis of3-fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

To a stirred solution of3-fluoro-5-(3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclo-penta[cd]inden-7-yl)oxy)benzonitrile(20 mg, 0.05 mmol, 1.00 equiv.) in THF (0.60 mL) was addedbromo(methyl)magnesium (1.0 M, 0.16 mL, 0.16 mmol, 3.05 equiv.) dropwiseat −78° C. under nitrogen atmosphere. The resulting mixture was stirredfor 1 h at −78° C. under nitrogen atmosphere, then quenched withsaturated NH₄Cl (aq.) (2 mL) at −78° C. The resulting mixture wasextracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified byPrep-HPLC to afford the title compound (10 mg, 48.0%) as a white solid.MS (ES, m/z): [M−H]⁻=396.2.

Example 9 Synthesis of3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

To a stirred mixture of3-fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile(30 mg, 0.07 mmol, 1.00 equiv.) in DCM (1.5 mL) was added DAST (12 mg,0.07 mmol, 1.00 equiv.) dropwise at −50° C. under nitrogen atmosphere.The resulting mixture was stirred for 1.5 h at −50-−40° C. undernitrogen atmosphere then quenched with saturated NaHCO₃ (aq.) at 0° C.The resulting mixture was extracted with DCM and the combined organiclayers were washed with water and dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure and thecrude was purified by Prep-HPLC to afford the title compound (4.3 mg,14.3%) as a white solid. MS (ES, m/z): [M−H]⁻=398.1.

Example 10 Synthesis of3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

Step 1:O-(7-(3-cyano-5-fluorophenoxy)-3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-yl)1H-imidazole-1-carbothioate

To a stirred solution of3-fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile(100 mg, 0.26 mmol, 1.00 equiv.) and DMAP (6 mg, 0.05 mmol, 0.20 equiv.)in DCE (2.0 mL) was added di(1H-imidazol-1-yl)methanethione (56 mg, 0.31mmol, 1.20 equiv.) at room temperature under nitrogen atmosphere. Theresulting mixture was stirred for 3 h at room temperature. The reactionmixture was concentrated and the residue was purified by Prep-TLC(PE/EtOAc 2:1) to afford the title compound (80 mg, 62%). MS (ES, m/z):[M+H]⁺=494.1.

Step 2:3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

To a stirred solution ofO-(7-(3-cyano-5-fluorophenoxy)-3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-yl)1H-imidazole-1-carbothioate (65 mg, 0.13 mmol, 1.00 equiv.) and Bu₃SnH(115 mg, 0.40 mmol, 3.00 equiv.) in toluene (2.0 mL) was added AIBN (65mg, 0.40 mmol, 3.00 equiv.) at room temperature under nitrogenatmosphere. The resulting mixture was stirred for 16 h at 50° C., cooledand diluted with water, and extracted with EtOAc. The combined organiclayers were washed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by Prep-TLC (PE/EtOAc=2/1) andPerp-HPLC to afford the title compound (12 mg, 25%) as a white solid. MS(ES, m/z): [M−H]⁻=366.2.

Example 11 Synthesis of3-((2a-amino-1,3,3,4,4-pentafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile

Step 1:N-(7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide

To a stirred mixture of7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (1.00 g, 3.32mmol, 1.00 equiv.) and 2-methylpropane-2-sulfinamide (0.81 g, 6.64 mmol,2.00 equiv.) in THF (20.0 mL) was added Ti(OEt)₄ (3.03 g, 13.29 mmol,4.00 equiv.) at room temperature. After stirring for 4 h at 75° C., thereaction mixture was cooled and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withEtOAc/PE (0-60%), to afford the title compound (900 mg, 67.0%) as abrown oil. MS (ES, m/z): [M+1]⁺=404.0.

Step 2:N-(1-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide

To a stirred solution ofN-(7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide(900 mg, 2.23 mmol, 1.00 equiv.) in THF (15.0 mL) was addedallylmagnesium bromide (2.0 M, 1.34 mL, 2.70 mmol, 1.20 equiv.) at 0° C.After stirring for 1.5 h at 0° C., the reaction mixture was quenchedwith saturated NH₄Cl (aq.) at 0° C. then extracted with EtOAc. Thecombined organic layers were washed with brine and dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with EtOAc/PE (0-50%), to afford the title compound (750 mg,75.5%) as a light yellow oil. MS (ES, m/z): [M+1]⁺=446.1.

Step 3:2-methyl-N-(3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]-inden-2a-yl)propane-2-sulfinamide

To a stirred mixture ofN-(1-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide(750 mg, 1.68 mmol, 1.00 equiv.) and Pd(dppf)Cl₂—CH₂Cl₂ (137 mg, 0.17mmol, 0.10 equiv.) in DMF (15.0 mL) was added NaOAc (414 mg, 5.05 mmol,3.00 equiv.) at room temperature under nitrogen atmosphere. Afterstirring for 1.5 h at 100° C., the reaction mixture was cooled to roomtemperature, quenched with water and extracted with EtOAc. The combinedorganic layers were washed with brine and dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith EtOAc/PE (10%-40%), to afford the title compound (450 mg, 73.3%) asa light yellow solid. MS (ES, m/z): [M+1]⁺=366.1.

Step 4:3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-amine

To a stirred solution of2-methyl-N-(3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-yl)propane-2-sulfinamide(150 mg, 0.41 mmol, 1.00 equiv.) in 1,4-dioxane (1.0 mL) was added asolution of HCl in 1,4-dioxane (4.0 M, 1.00 mL, 4.0 mmol, 9.74 equiv.)at room temperature. After stirring for 5 h at room temperature, thereaction mixture was quenched with NaHCO₃ (aq.) at room temperature andextracted with EtOAc. The combined organic layers were washed with brineand dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with EtOAc/PE (0-60%), to afford thetitle compound (85 mg, 79.3%) as a light yellow oil. MS (ES, m/z):[M+1]⁺=262.1.

Step 5:2a-amino-3,3,4,4,7-pentafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one

To a stirred mixture of3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-amine(85 mg, 0.325 mmol, 1.00 equiv.) and NaIO₄ (278 mg, 1.30 mmol, 4.00equiv.) in CH₃CN (0.50 mL) and DCM (0.50 mL) were added water (0.75 mL)and RuCl₃·H₂O (7.34 mg, 0.03 mmol, 0.10 equiv.) at room temperature.After stirring for 1 h at room temperature, the resulting mixture wasdiluted with DCM. The organic layer was washed with brine and dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure and the residue was purified by Prep-TLC (PE/EtOAc=3/1)to afford the title compound (45 mg, 52.5%) as a light yellow oil. MS(ES, m/z): [M−1]⁻=261.9.

Step 6:3-((2a-amino-3,3,4,4-tetrafluoro-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile

To a stirred mixture of2a-amino-3,3,4,4,7-pentafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one(40 mg, 0.15 mmol, 1.00 equiv.) and 3-fluoro-5-hydroxybenzonitrile (21mg, 0.15 mmol, 1.00 equiv.) in DMF (1.00 mL) was added Cs₂CO₃ (50 mg,0.15 mmol, 1.00 equiv.) at room temperature. After stirring for 1.5 h atroom temperature, the reaction was quenched with water and extractedwith EtOAc. The combined organic layers were washed with brine and driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by Prep-TLC(PE/EtOAc=3/1) to afford the title compound (35 mg, 60.3%) as a whitesolid. MS (ES, m/z): [M+1]⁺=381.1.

Step 7:3-((2a-amino-3,3,4,4-tetrafluoro-1-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile

To a stirred solution of3-((2a-amino-3,3,4,4-tetrafluoro-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile(35 mg, 0.09 mmol, 1.00 equiv.) in MeOH (0.50 mL) was added NaBH₄ (5 mg,0.13 mmol, 1.4 equiv.) at room temperature. After stirring for 0.5 h atroom temperature, the reaction mixture was quenched with saturated NH₄Cl(aq.) at 0° C. and extracted with EtOAc. The combined organic layerswere washed with brine and dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withEtOAc/PE (0-60%), to afford the title compound (30 mg, 85.3%) as a lightyellow oil. MS (ES, m/z): [M+1]⁺=383.1.

Step 8:3-((2a-amino-1,3,3,4,4-pentafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile

To a stirred solution of3-((2a-amino-3,3,4,4-tetrafluoro-1-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile(25 mg, 0.07 mmol, 1.00 equiv.) in DCM (1.0 mL) was added DAST (16 mg,0.10 mmol, 1.5 equiv.) at room temperature. After stirring for 2 h atroom temperature, the reaction mixture was quenched with saturatedNaHCO₃ (aq.) at 0° C. and extracted with DCM. The combined organiclayers were washed with brine and dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated and purified by Prep-HPLC toafford the title compound (6 mg, 24%) as a white solid. MS (ES, m/z):[M+1]⁺=385.1.

Example 12 Synthesis of3-fluoro-5-((1,1,2a,3,3,4,4-heptafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

To a stirred mixture of3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclo-penta[cd]inden-7-yl)oxy)benzonitrile(30 mg, 0.08 mmol, 1.00 equiv.) in DCM (1.0 mL) were added4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (59 mg, 0.24 mmol,3.00 equiv.) and pyridine hydrofluoride (0.05 mL, 65%-70%) at roomtemperature. The resulting mixture was stirred for 24 h at roomtemperature under nitrogen atmosphere then diluted with water andextracted with DCM. The combined organic layers were washed with waterand dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated and purified by Prep-HPLC to afford the title compound (9.9mg, 31.1%) as a white solid. MS (ES, m/z): [M−H]⁻=404.1.

Example 13 Synthesis of3-((3,3-difluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile

Step 1:3-fluoro-5-((7-iodo-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

Into a 2 L round-bottom flask were added3-fluoro-5-((1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile (28 g,104.77 mmol, 1.00 equiv.), F-TEDA-BF₄ (33 g, 93.15 mmol, 0.89 equiv.)and CH₃CN (840 mL). To this stirred solution was added a solution of12(24 g, 94.56 mmol, 0.90 equiv.) in CH₃CN (560 mL) dropwise at 60° C.The resulting mixture was stirred for 3 h at 60° C. The mixture wascooled to room temperature then concentrated under vacuum. To theresidue was added ethyl acetate (250 mL) and the resulting mixture wasstirred for 1 h at 80° C. The mixture was cooled to room temperature andthe precipitated solids were collected by filtration and washed withEt₂O to afford the tittle compound (16.8 g, 40.8%) as an off-whitesolid. MS (ES, m/z): [M+H]⁺=394.0.

Step 2:3-((2,2-difluoro-7-iodo-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

To a stirred mixture of3-fluoro-5-((7-iodo-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-benzonitrile(3.600 g, 9.15 mmol, 1.00 equiv.) and butan-1-amine (6.7 g, 91.57 mmol,10.00 equiv.) in toluene (90 mL) was added TFA (209 mg, 1.83 mmol, 0.20equiv.) dropwise at room temperature. The resulting mixture was stirredfor 16 h at 100° C. under nitrogen atmosphere then concentrated undervacuum. The residue was dissolved in CH₃CN (90 mL), followed by theaddition of Na₂SO₄ (5.2 g, 36.62 mmol, 4.00 equiv.) and F-TEDA-BF₄ (6.5g, 18.31 mmol, 2.00 equiv.) at room temperature. The resulting mixturewas stirred for 2 h at 80° C., diluted with water and extracted withEtOAc. The combined organic layers were washed with water, brine, anddried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE/EtOAc (10:1), to afford (1.60g, 40.7%) of the title compound as a yellow solid.

Step 3:3-((1-allyl-2,2-difluoro-1-hydroxy-7-iodo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

To a stirred mixture of3-((2,2-difluoro-7-iodo-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(449 mg, 1.05 mmol, 1.00 equiv.) and allylbromide (253.15 mg, 2.093mmol, 2.00 equiv.) in THF (10 mL) were added pyridine (165.52 mg, 2.09mmol, 2.00 equiv.) and (1S,2R)-2-amino-1,2-diphenylethanol (446.30 mg,2.09 mmol, 2.00 equiv.) at room temperature. Indium powder (240.26 mg,2.09 mmol, 2.00 equiv.) was then added into the solution and theresulting mixture was stirred for 8 h at room temperature under nitrogenatmosphere. The resulting mixture was filtered and the filter cake waswashed with EtOAc. The filtrate was concentrated and purified by silicagel column chromatography, eluted with PE/EtOAc (9:1), to afford thetittle compound (430 mg, 87.2%) as a yellow oil. MS (ES, m/z):[M−H]⁻=470.0.

Step 4:3-((3,3-difluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile

To a stirred solution of3-((1-allyl-2,2-difluoro-1-hydroxy-7-iodo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile(430 mg, 0.91 mmol, 1.00 equiv.) and NaOAc (225 mg, 2.74 mmol, 3.00equiv.) in DMF (10 mL) was added Pd(dppf)Cl₂CH₂Cl₂ (75 mg, 0.09 mmol,0.10 equiv.) at room temperature under nitrogen atmosphere. Theresulting mixture was stirred for 3 h at 100° C. under nitrogenatmosphere then filtered. The filter cake was washed with EtOAc and thefiltrate was washed with H₂O, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (5:1), to afford the title compound(223 mg, 71.2%) as a yellow oil.

Example 14 Synthesis of3-((3,3-difluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile

Into a 25 mL 2-necked round-bottom flask were added3-((3,3-difluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile(210 mg, 0.61 mmol, 1.00 equiv.), DCM (2.0 mL), MeCN (2.0 mL) and H₂O(3.0 mL) at room temperature. RuCl₃·H₂O (7 mg, 0.03 mmol, 0.05 equiv.)was then added into the solution. To the above mixture was added NaIO₄(523 mg, 2.45 mmol, 4.00 equiv.) in portions over 2 min at roomtemperature and the resulting mixture was stirred for 3 h at roomtemperature. The resulting mixture was extracted with DCM and thecombined organic layers were washed with Na₂S₂O₃ (aq.), H₂O and brine,and dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE/EtOAc (5:1), to afford thetittle compound (107 mg, 50.7%) as a yellow oil. MS (ES, m/z):[2M−H]⁻=689.1.

Example 15 Synthesis of3-((3,3-difluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile

Into an 8 mL sealed tube were added3-((3,3-difluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile(100 mg, 0.29 mmol, 1.00 equiv.) and MeOH (2.00 mL) at room temperature.To the above mixture was added NaBH₄ (22 mg, 0.58 mmol, 2.0 equiv.) inportions at 0° C. and the resulting mixture was stirred for 1 h at roomtemperature. The reaction was quenched with water at 0° C. andneutralized to pH=7 with aqueous HCl (1.0 M). The resulting mixture wasextracted with DCM and the combined organic layers were dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated andpurified by Prep-TLC (PE/EtOAc=5/1) to afford the tittle compound (78mg, 77.6%) as a white solid.

Example 16 Synthesis of3-fluoro-5-((1,3,3-trifluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

To a stirred solution of3-((3,3-difluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile(20 mg, 0.06 mmol, 1.00 equiv.) in THF (0.50 mL) was added a solution ofDAST (9.35 mg, 0.06 mmol, 1.00 equiv.) in DCM (0.2 mL) dropwise at −50°C. under nitrogen atmosphere. The resulting mixture was stirred for 1 hat −50° C. under nitrogen atmosphere then quenched with water at −40° C.The mixture was neutralized to pH=7 with saturated NaHCO₃ (aq.) thenextracted with EtOAc. The combined organic layers were washed with brineand dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated and purified by Prep-HPLC to afford the title compound (5.7mg, 28.3%) as a white solid. MS (ES, m/z): [2M−H]⁻=697.2.

Example 17 Synthesis of3-fluoro-5-((1,1,2,2,3,3,4-heptafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

Step 1: ethyl2,2-difluoro-2-(2,2,3,3,6-pentafluoro-1-hydroxy-2,3-dihydro-1H-inden-1-yl)acetate

A mixture of 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (10.0 g,45.02 mmol, 1.00 equiv.), In (7.7 g, 67.06 mmol, 1.5 equiv.) and ethyl2-bromo-2,2-difluoroacetate (13.7 g, 67.5 mmol, 1.50 equiv.) in THF (150mL) was stirred for 16 h at 60° C. under N₂ atmosphere. The reaction wasquenched with aqueous HCl (2.0 M, 50 mL) at room temperature and theresulting mixture was extracted with ethyl acetate. The combined organiclayers were dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with PE/EA (5/1), to afford thetitle compound (8.0 g, 51.3%) as a light-yellow oil. MS (ES, m/z):[M−1]⁻=345.0 Step 2:1,1,2,2,3,3,5-heptafluoro-2a-hydroxy-1,2,2a,3-tetrahydro-4H-cyclopenta[cd]inden-4-one

To a stirred solution of ethyl2,2-difluoro-2-(2,2,3,3,6-pentafluoro-1-hydroxy-2,3-dihydro-1H-inden-1-yl)acetate(500 mg, 1.44 mmol, 1.00 equiv.) in THF (10 mL) was added LDA (2.2 mL,4.40 mmol, 2.0 M, 3.06 equiv.) dropwise at −78° C. under N₂ atmosphere.The resulting mixture was stirred for 1 h at −78° C. and then quenchedwith saturated aqueous NH₄Cl (10 mL) at −78° C. The resulting mixturewas extracted with ethyl acetate and the combined organic layers weredried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated and purified by silica gel column chromatography, elutedwith PE/EA (3/1), to afford crude product. The crude product waspurified by Prep-HPLC to afford the title product (34 mg, 7.8%) as alight-yellow oil. MS (ES, m/z): [M−1]⁻=298.9

Step 3:3-fluoro-5-((1,1,2,2,3,3-hexafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

A mixture of1,1,2,2,3,3,5-heptafluoro-2a-hydroxy-1,2,2a,3-tetrahydro-4H-cyclopenta-[cd]inden-4-one(100 mg, 0.33 mmol, 1.00 equiv.), Cs₂CO₃ (217 mg, 0.67 mmol, 2.00equiv.) and 3-fluoro-5-hydroxybenzonitrile (50 mg, 0.36 mmol, 1.10equiv.) in DMF (2 mL) was stirred for 1 h at −10° C. under N₂atmosphere. The crude reaction mixture was used for next step directlywithout further purification. MS (ES, m/z): [M−1]⁻=416.0.

Step 4:3-fluoro-5-((1,1,2,2,3,3-hexafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

To a stirred solution of crude3-fluoro-5-((1,1,2,2,3,3-hexafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile(0.33 mmol, 1.00 equiv.) in MeOH (2 mL) was added NaBH₄ (25 mg, 0.66mmol, 2.00 equiv.) in portions at −10° C. under N₂ atmosphere. Theresulting mixture was stirred for 1 h at −10° C. and then quenched withsaturated aqueous NH₄Cl solution. The resulting mixture was extractedwith ethyl acetate and the combined organic layers were washed withbrine, and dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with PE/EA (3/1), to afford thetitle compound (90 mg, 63.6%) for two steps as a light-yellow oil. MS(ES, m/z): [M−1]⁻=418.0.

Step 5:3-fluoro-5-((1,1,2,2,3,3,4-heptafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

To a stirred solution of3-fluoro-5-((1,1,2,2,3,3-hexafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile(50 mg, 0.12 mmol, 1.00 equiv.) in DCM (1.0 mL) was added DAST (38 mg,0.24 mmol, 2.00 equiv.) dropwise at −20° C. under N₂ atmosphere. Theresulting mixture was stirred for 2 h at room temperature, quenched withsaturated aqueous NaHCO₃ solution. The resulting mixture was extractedwith DCM and the combined organic layers were dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure and the crude product was purified by Prep-HPLC to afford thetitle compound (14 mg, 27.5%) as a light yellow solid. MS (ES, m/z):[M−1]⁻=420.0.

Example 18 Synthesis of3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)benzonitrile

Step 1: (R)-1-allyl-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol

To a stirred solution of t-BuONa (21.6 mg, 0.225 mmol, 0.10 equiv.) intoluene (3.0 mL) were added a solution of(S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethylbutanamide(275.8 mg, 0.90 mmol, 0.40 equiv.) in toluene (0.5 mL), then a solutionof MeOH (90.2 mg, 2.8 mmol, 1.25 equiv.) in toluene (0.5 mL), followedby a solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (0.50g, 2.25 mmol, 1.00 equiv.) in toluene (0.5 mL). After stirring for 15min at room temperature, a solution of4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane (416.1 mg,2.48 mmol, 1.10 equiv.) in toluene (0.5 mL) was added slowly. Theresulting mixture was stirred for 6.5 h at 60° C., cooled and dilutedwith ethyl acetate. After separation, the organic layer was washed withwater and brine, dried over Na₂SO₄. After filtration, the filtrate wasconcentrated and purified by silica gel column chromatography, elutedwith DCM/PE (0-40%), to afford the title compound (0.52 g, 87.4%) as alight yellow oil. MS (ES, m/z): [M−1]⁻=263.0.

Step 2: (1R)-7-bromo-2,2,3,3,6-pentafluoro-1-(prop-2-en-1-yl)inden-1-ol

To a stirred solution of(R)-1-allyl-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol (5.0 g,18.93 mmol, 1.00 equiv.) in tetrahydrofuran (60 mL) was added 2.0 M LDA(28.4 mL, 56.8 mmol, 3.0 equiv.) dropwise at −40° C. under nitrogenatmosphere. After stirring for 1 h at −40° C., a solution of carbontetrabromide (7.53 g, 22.71 mmol, 1.20 equiv.) in THF was added dropwiseat −40° C. The resulting mixture was stirred for additional 10 min at−40° C., then quenched with 1.0 M HCl (aq.) (100 mL) at −40° C. Theresulting mixture was extracted with MTBE. The organic layer was washedwith water and brine, dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated and purified by silica gel columnchromatography, eluted with EtOAc/PE (0-30%), to afford the crudeproduct as light yellow oil. This crude product was further purified byreversed-phase C18 silica gel column (mobile phase, ACN in water, 50% to95% gradient in 12 min) to afford the title compound (3.5 g, 53.9%) as alight yellow oil. MS (ES, m/z): [M−1]⁻=340.9.

Step 3:(R)-3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol

To a stirred mixture of(R)-1-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol(3.50 g, 10.20 mmol, 1.00 equiv.) in DMF (5.0 mL) were added AcONa (2.51g, 30.60 mmol, 3.00 equiv.) and Pd(dppf)C₂·CH₂Cl₂ (0.83 g, 1.02 mmol,0.10 equiv.) at room temperature under nitrogen atmosphere. Theresulting mixture was stirred for 3 h at 100° C. under nitrogenatmosphere, cooled and diluted with water, then extracted with ethylacetate. The organic layer was washed with water and brine, dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated andpurified by silica gel column chromatography, eluted with EtOAc/PE(0-40%), to afford the title compound (2.0 g, 74.8%) as a light yellowsolid. MS (ES, m/z): [M−1]⁻=260.9.

Step 4:(R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one

To a stirred mixture of(R)-3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol (2.00 g, 7.63 mmol, 1.00 equiv.) in a mixed solvents(DCM/MeCN/H₂O=1/1/1.5, 70.0 mL) was added RuCl₃·H₂O (86.0 mg, 0.38 mmol,0.05 equiv.) at room temperature. To the resulting mixture was addedNaIO₄ (6.53 g, 30.53 mmol, 4.0 equiv.) in portions at room temperature.After stirring for 1 h at room temperature, the reaction mixture wasdiluted with water, then extracted with DCM. The organic layer waswashed with saturated Na₂S₂O₃ (aq.), water and brine, dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated toafford crude title compound (1.85 g, 91.8%) as a light yellow solid,which was used for next step without further purification. MS (ES, m/z):[M−1]⁻=262.9.

Step 5:(R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

To a stirred solution of(R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one (1.85 g, 7.0 mmol, 1.00 equiv.) and3-fluoro-5-hydroxybenzonitrile (0.86 g, 6.30 mmol, 0.90 equiv.) in DMF(20.0 mL) was added Cs₂CO₃ (2.28 g, 7.00 mmol, 1.00 equiv.) at roomtemperature. After stirring for 16 h at room temperature, the reactionmixture was quenched with water at 0° C., then extracted with EtOAc. Theorganic layer was washed with water and brine, dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated and purified bysilica gel column chromatography, eluted with EtOAc/PE (0-40%), toafford the title compound (1.95 g, 73.0%) as a white solid. MS (ES,m/z): [M-1]−=380.1.

Step 6:(R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-2,2-d2)oxy)benzonitrile

To a stirred mixture of(R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile(3.0 g, 7.87 mmol, 1.00 equiv.) in THF (60 mL) was added a solution ofNaOD (645 mg, 15.737 mmol, 2.00 equiv.) in D₂O (24 mL) dropwise at roomtemperature. The resulting mixture was stirred for 4 h at roomtemperature then diluted with D₂O and extracted with MTBE. The combinedorganic layers were dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography, eluted with PE/EA (3:1),to afford the title compound (2.3 g, 76.3%) as a white solid. MS (ES,m/z): [M−H]⁻=382.1.

Step 7:3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)benzonitrile

To a stirred mixture of(R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-2,2-d2)oxy)benzonitrile(1.5 g, 3.883 mmol, 1.00 equiv.) in CD3OD (15 mL) was added NaBD₄ (329mg, 7.827 mmol, 2.00 equiv.) at 5° C. The resulting mixture was stirredfor 2 h at room temperature then quenched with D₂O at room temperature.The resulting mixture was extracted with MTBE and the combined organiclayers were dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure and the residue was purified bysilica gel column chromatography, eluted with PE/EA (3:1), to afford thetitle compound (1.5 g, 99.2%) as a light yellow solid. MS (ES, m/z):[M−H]⁻=385.1.

Step 8:3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)benzonitrile

To a stirred mixture of3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)benzonitrile(1.5 g, 3.88 mmol, 1.00 equiv.) in THF (21 mL) were added DBU (1.18 g,7.77 mmol, 2.00 equiv.) and pyridine-2-sulfonyl fluoride (814 mg, 5.05mmol, 1.30 equiv.) in THF (2 mL) dropwise at room temperature undernitrogen atmosphere. The resulting mixture was stirred for 16 h at roomtemperature under nitrogen atmosphere then concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith PE/EA (4:1). The resulting product was further purified by chiralPrep-HPLC to afford the optical pure title compound (740 mg, 49.1%) as awhite solid. MS (ES, m/z): [M−H]⁻=387.1.

Example 19 Synthesis of3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)oxy)benzonitrile-2,4,6-d₃

Step 1: 3-bromo-5-fluorophen-2,4,6-d₃-ol

Into a 40 mL sealed tube were added 3-bromo-5-fluorophenol (5.00 g,26.18 mmol, 1.00 equiv.) and 60% D₂SO₄ (13.09 g, 78.53 mmol, 3.00equiv.) in D₂O at room temperature. The resulting mixture was stirredfor 18 h at 75° C. then poured slowly onto ice. The resulting mixturewas extracted with EtOAc and the combined organic layers were washedwith water, brine and dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure to give the product.The product was added in 60% D₂SO₄ in D₂O, and the above procedure wasrepeated for additional 4 times to give the tittle compound (4.20 g,82.7% yield) as yellow oil. MS (ES, m/z): [M−H]⁻=191.9.

Step 2: 3-fluoro-5-hydroxybenzonitrile-2,4,6-d₃

To a stirred solution of 3-bromo-5-fluorophen-2,4,6-d₃-ol (100 mg, 0.515mmol, 1.00 equiv.) and Zn(CN)₂ (121 mg, 1.03 mmol, 2.0 equiv.) in DMF(2.0 mL) was added Pd(PPh₃)₄ (60 mg, 0.05 mmol, 0.10 equiv.) at roomtemperature under nitrogen atmosphere. The resulting mixture was stirredfor 3 h at 100° C. under nitrogen atmosphere and then quenched withwater at room temperature. The resulting mixture was extracted withEtOAc and the combined organic layers were washed with water, brine, anddried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE/EtOAc (1:1), to afford thetitle compound (37 mg, 51.2%) as a white solid. MS (ES, m/z):[M−H]⁻=139.0.

Step 3:(R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile-2,4,6-d₃

To a stirred mixture of(R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one(179 mg, 0.68 mmol, 1.00 equiv.) and3-fluoro-5-hydroxybenzonitrile-2,4,6-d₃ (95 mg, 0.68 mmol, 1.00 equiv.)in DMF (3.5 mL) was added Cs₂CO₃ (221 mg, 0.68 mmol, 1.00 equiv.) atroom temperature. After stirring for 16 h at room temperature, thereaction mixture was quenched with water at 0° C. The resulting mixturewas extracted with EtOAc and the combined organic layers were washedwith H₂O, brine and dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with EtOAc/PE(0-40%), to afford the tittle compound (170 mg, 65.3%) as a white solid.MS (ES, m/z): [M−H]⁻=383.0.

Step 4:3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)oxy)benzonitrile-2,4,6-d₃

To a stirred mixture of(R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile-2,4,6-d₃(170 mg, 0.442 mmol, 1.00 equiv.) in CD3OD (3.5 mL) was added NaBD₄ (37mg, 0.885 mmol, 2.00 equiv.) in portions at room temperature. Theresulting mixture was stirred for 3 h at room temperature, diluted withD₂O (3.0 mL) and extracted with EtOAc. The combined organic layers weredried over anhydrous Na₂SO₄, and filtered. The filtrate was concentratedand and the residue was purified by silica gel column chromatography,eluted with EtOAc/PE (0-40%), to afford the tittle compound (120 mg,70.0%) as a white solid. MS (ES, m/z): [2M−H]⁻=773.1.

Step 5:3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)oxy)benzonitrile-2,4,6-d₃

To a stirred mixture of3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)oxy)benzonitrile-2,4,6-d₃(125 mg, 0.32 mmol, 1.00 equiv.) in THF (1.6 mL) were added DBU (98 mg,0.65 mmol, 2.00 equiv.) and pyridine-2-sulfonyl fluoride (68 mg, 0.42mmol, 1.30 equiv.) in THF (0.4 mL) dropwise at room temperature undernitrogen atmosphere. The resulting mixture was stirred for 16 h at roomtemperature under nitrogen atmosphere. The reaction solution waspurified by silica gel column chromatography, eluted with PE/EtOAc(4:1), followed by purification with prep-HPLC to afford the tittlecompound (10 mg, 8.0%) as a white solid. MS (ES, m/z): [M−H]⁻=388.1.

Example 20 Synthesis of(R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile[23a] and(S)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile[23b]

To a stirred mixture of(R)-3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol(400 mg, 1.53 mmol, 1.0 equiv, ˜80% ee) and3-fluoro-5-hydroxybenzonitrile (209 mg, 1.53 mmol, 1.0 equiv) in DMF (10mL) was added Cs₂CO₃ (497 mg, 1.53 mmol, 1.0 equiv) at room temperatureand the resulting mixture was stirred for 24 h at 100° C. After coolingthe reaction mixture to room temperature, it was filtered. The filtratewas purified by Prep-HPLC to afford 131 mg of product as a mixture ofenantiomers. The enantiomers were separated by Chiral pre-HPLC [Column:CHIRALPAK OD-3, 50*4.6 mm, 3 um OD3OCC-QE001, flow rate: 1.0 mL/min;oven temperature: 25° C.; Mobile Phase A: n-hexanes; Mobile Phase B:ethanol; conc. of Phase B: 10%) to afford 23a (65 mg, 11.2%) MS (ES,m/z): [M−H]⁻=378.0. tR: 1.34 min and 23b (6 mg, 1.0%); MS (ES, m/z):[M−H]⁻=378.0. tR: 1.77 min.

Example 21 Synthesis of3-fluoro-5-(((2aS,3S)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile[24a] and3-fluoro-5-(((2aS,3R)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile [24b]

Step 1:(R)-3-((4-(butylimino)-1,1,2,2-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile

A solution of(R)-3-fluoro-5-((1,1,2,2-tetrafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile (700 mg, 1.84 mmol, 1.0 equiv., ˜80% ee),TFA (42 mg, 0.37 mmol, 0.2 equiv.) and butylamine (1343 mg, 18.36 mmol,10.0 equiv.) in toluene (15 mL) was stirred for 16 h at 100° C. under N₂atmosphere. The resulting mixture was concentrated under vacuum toafford the title compound (1.0 g, crude) as a light brown oil, which wasused for next step directly. MS (ES, m/z): [M+1]⁺=437.2.

Step 2: 3-fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile and3-fluoro-5-(((2aS,3R)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

A mixture of(R)-3-((4-(butylimino)-1,1,2,2-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile(1.0 g crude, 1.84 mmol, 1.0 equiv.), sodium sulfate (651 mg, 4.58 mmol,2.5 equiv.) and Selectfluor (1.05 g, 2.96 mmol, 1.6 equiv.) in MeCN (15mL) was stirred for 4 h at 60° C. under N₂ atmosphere. The crude productwas purified by Prep-HPLC to afford 150 mg of one isomer and 300 mg ofthe other isomer. MS (ES, m/z): [M−1]⁻=397.9.

Step 3:3-fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrileand3-fluoro-5-(((2aS,3R)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

3-Fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrileor3-fluoro-5-(((2aS,3R)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrilewere converted to3-fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrileor3-fluoro-5-(((2aS,3R)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile,respectively as follows.

To a stirred solution of3-fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrileor3-fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile(1.0 equiv.) in MeOH was added NaBH₄ (2.0 equiv.) in portions at 0° C.under N₂ atmosphere. The resulting mixture was stirred for 1 h at roomtemperature the quenched with saturated aqueous NH₄Cl solution. Theresulting mixture was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure toafford3-fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrileor3-fluoro-5-(((2aS,3R)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrilerespectively, as a light yellow oil. MS (ES, m/z): [2M-1]⁻=801.2.

Step 4:3-fluoro-5-(((2aS,3S)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrileor3-fluoro-5-(((2aS,3R)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

3-Fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrileor3-fluoro-5-(((2aS,3R)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrilewere converted to3-fluoro-5-(((2aS,3S)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrileor3-fluoro-5-(((2aS,3R)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrileas follows.

To a stirred solution of3-fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrileor3-fluoro-5-(((2aS,3R)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile(1.0 equiv.) in DCM was added DAST (1.5 equiv.) dropwise at −40° C.under N₂ atmosphere. The resulting mixture was stirred for 2 h at −40°C., quenched with saturated aqueous NH₄Cl solution. The resultingmixture was extracted with DCM. The combined organic layers were driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure. The crude product was purified by Prep-HPLC toafford3-fluoro-5-(((2aS,3S)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrileor3-fluoro-5-(((2aS,3R)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrilerespectively as a light yellow solid. MS (ES, m/z): [M−1]⁻=402.0.

Since the stereochemistry at *C of compound 24a and 24b has not beendetermined, compound 24a is either be compound 24a1 or 24a2.

Similarly, compound 24b is compound 24b1 or 24b2.

BIOLOGICAL EXAMPLES Example 1 VEGF ELISA Assay

The ability of the disclosed compounds to inhibit HIF-2α was measured bydetermining VEGF expression in 786-0 cells. About 7500 786-O cells wereseeded into each well of a 96-well, white, clear bottom plate(07-200-566, Fisher Scientific) with 200 ul growth medium. Four hourslater, compounds were dispensed into wells by Tecan D300e digitaldispenser with starting concentration of 10 uM and ½ log of dilutiondown to 1 nM as final concentration. Each concentration of treatment wasperformed in duplicate. About 20 hours later, medium was removed andfresh medium was added, followed by compounds treatment as describedabove. 24 hours later, cell culture medium was collected to determineVEGF concentration using an ELISA kit (R&D systems, cat #DVE00)following the manufacturer's instruction.

The EC₅₀ is calculated by GraphPad Prism using thedose-response-inhibition (four parameter) equation. The plate with cellswas then subjected to CellTiter-Glo luminescence cell viability assay(Promega) to determine the effect of these compounds on cell numbersafter the above treatment.

Compound No. as EC₅₀ in Cpd. Table 1 (μM)  1 0.013  4 0.010  5 0.006  72.10  8 0.32  9 0.17 10 0.41 11 >5 12 0.10 13 0.33 14 0.63 15 >5 19 4.121 0.006 23a 0.007

FORMULATION EXAMPLES

The following are representative pharmaceutical formulations containinga compound of the present disclosure.

Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets.

Ingredient Quantity per tablet (mg) compound of this disclosure 400cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Ingredient Quantity per capsule (mg) compound of this disclosure 200lactose spray dried 148 magnesium stearate 2

Injectable Formulation

Compound of the disclosure (e.g., a compound of formula I) in 2% HPMC,1% Tween 80 in DI water, q.s. to at least 20 mg/mL

Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound disclosed herein is mixed with 50 mg of anhydrous citricacid and 100 mL of 0.9% sodium chloride solution. The mixture isincorporated into an inhalation delivery unit, such as a nebulizer,which is suitable for inhalation administration.

Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound disclosed herein is mixed with 1.75 g of hydroxypropylcellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and100 mL of purified alcohol USP. The resulting gel mixture is thenincorporated into containers, such as tubes, which are suitable fortopical administration.

Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound disclosed herein is mixed with 0.9 g of NaCl in 100 mL ofpurified water and filtered using a 0.2 micron filter. The resultingisotonic solution is then incorporated into ophthalmic delivery units,such as eye drop containers, which are suitable for ophthalmicadministration.

Nasal Spray Solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compounddisclosed herein is mixed with 30 mL of a 0.05M phosphate buffersolution (pH 4.4). The solution is placed in a nasal administratordesigned to deliver 100 ul of spray for each application.

What is claimed:
 1. A compound selected from the group consisting of:3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]-inden-7-yl)oxy)benzonitrile,according to the following structure:

3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile,according to the following structure:

3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)benzonitrile,according to the following structure:

and3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)oxy)benzonitrile-2,4,6-d3,according to the following structure:

or a pharmaceutically acceptable salt thereof.
 2. Compound is3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile,according to the following structure:


3. The compound of claim 1, wherein the compound is3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile,according to the following structure:


4. The compound of claim 1, wherein the compound is3-fluoro-5-(((1R,2aS)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile,according to the following structure:


5. The compound of claim 1, wherein the compound is3-fluoro-5-(((1R,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile, according to the following structure:


6. The compound of claim 1, wherein the compound is3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)-benzonitrile,according to the following structure:


7. The compound of claim 1, wherein the compound is3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)-oxy)benzonitrile-2,4,6-d3,according to the following structure:


8. The compound of claim 1, wherein the compound is a pharmaceuticallyacceptable salt of3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile,according to the following structure:


9. The compound of claim 1, wherein the compound is a pharmaceuticallyacceptable salt of3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]-inden-7-yl)oxy)benzonitrile,according to the following structure:


10. The compound of claim 1, wherein the compound is a pharmaceuticallyacceptable salt of3-fluoro-5-(((1R,2aS)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]-inden-7-yl)oxy)benzonitrile,according to the following structure:


11. The compound of claim 1, wherein the compound is a pharmaceuticallyacceptable salt of3-fluoro-5-(((1R,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]-inden-7-yl)oxy)benzonitrile,according to the following structure:


12. The compound of claim 1, wherein the compound is a pharmaceuticallyacceptable salt of3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]-inden-7-yl-1,2,2-d3)oxy)-benzonitrile,according to the following structure:


13. The compound of claim 1, wherein the compound is a pharmaceuticallyacceptable salt of3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]-inden-7-yl-1-d)oxy)benzonitrile-2,4,6-d3,according to the following structure:


14. A pharmaceutical composition comprising a compound selected from thegroup consisting of:3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]-inden-7-yl)oxy)benzonitrile,according to the following structure:

3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile,according to the following structure:

3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)benzonitrile,according to the following structure:

and3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)oxy)benzonitrile-2,4,6-d-3,according to the following structure:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 15. A pharmaceutical composition comprising3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile,according to the following structure:

and a pharmaceutically acceptable excipient.
 16. The pharmaceuticalcomposition of claim 14, wherein the compound is3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile,according to the following structure:


17. The pharmaceutical composition of claim 14, wherein the compound isa pharmaceutically acceptable salt of3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile,according to the following structure:


18. The pharmaceutical composition of claim 14, wherein the compound isa pharmaceutically acceptable salt of3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile,according to the following structure:


19. The pharmaceutical composition of claim 14, wherein the compound is3-fluoro-5-(((1R,2aS)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile,according to the following structure:


20. The pharmaceutical composition of claim 14, wherein the compound is3-fluoro-5-(((1R,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile,according to the following structure:


21. The pharmaceutical composition of claim 14, wherein the compound is3-fluoro-5-(((1S,2aR)-((1,3,3,4,4-pentafluoro-2a-hydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)benzonitrile,according to the following structure:


22. The pharmaceutical composition of claim 14, wherein the compound is3-fluoro-5-(((1S,2aR)1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)oxy)benzonitrile-2,4,6-d3,according to the following structure:


23. The pharmaceutical composition of claim 14, wherein the compound isa pharmaceutically acceptable salt of3-fluoro-5-(((1R,2aS)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile,according to the following structure:


24. The pharmaceutical composition of claim 14, wherein the compound isa pharmaceutically acceptable salt of3-fluoro-5-(((1R,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile,according to the following structure:


25. The pharmaceutical composition of claim 14, wherein the compound isa pharmaceutically acceptable salt of3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)benzonitrile,according to the following structure:


26. The pharmaceutical composition of claim 14, wherein the compound isa pharmaceutically acceptable salt of3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)oxy)benzonitrile-2,4,6-d3,according to the following structure: